Glucocorticoid mimetics, methods of making them, pharmaceutical compositions, and uses thereof

ABSTRACT

Compounds of Formula (I)  
                 
 
wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7  are as defined herein, or a tautomer, prodrug, solvate, or salt thereof; pharmaceutical compositions containing such compounds, and methods of modulating the glucocorticoid receptor function and methods of treating disease-states or conditions mediated by the glucocorticoid receptor function or characterized by inflammatory, allergic, or proliferative processes in a patient using these compounds.

RELATED APPLICATIONS

This application claims benefit of U.S. Ser. No. 60/639,368, filed Dec.27, 2004, which is hereby incorporated by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to glucocorticoid mimetics or ligands,methods of making such compounds, their use in pharmaceuticalcompositions, and their use in modulating the glucocorticoid receptorfunction, treating disease-states or conditions mediated by theglucocorticoid receptor function in a patient in need of such treatment,and other uses.

BACKGROUND OF THE INVENTION

Glucocorticoids, a class of corticosteroids, are endogenous hormoneswith profound effects on the immune system and multiple organ systems.They suppress a variety of immune and inflammatory functions byinhibition of inflammatory cytokines such as IL-1, IL-2, IL-6, and TNF,inhibition of arachidonic acid metabolites including prostaglandins andleukotrienes, depletion of T-lymphocytes, and reduction of theexpression of adhesion molecules on endothelial cells (P. J. Barnes,Clin. Sci., 1998, 94, pp. 557-572; P. J. Barnes et al., TrendsPharmacol. Sci., 1993, 14, pp. 436-441). In addition to these effects,glucocorticoids stimulate glucose production in the liver and catabolismof proteins, play a role in electrolyte and water balance, reducecalcium absorption, and inhibit osteoblast function.

The anti-inflammatory and immune suppressive activities of endogenousglucocorticoids have stimulated the development of syntheticglucocorticoid derivatives including dexamethasone, prednisone, andprednisolone (L. Parente, Glucocorticoids, N. J. Goulding and R. J.Flowers (eds.), Boston: Birkhauser, 2001, pp. 35-54). These have foundwide use in the treatment of inflammatory, immune, and allergicdisorders including rheumatic diseases such as rheumatoid arthritis,juvenile arthritis, and ankylosing spondylitis, dermatological diseasesincluding psoriasis and pemphigus, allergic disorders including allergicrhinitis, atopic dermatitis, and contact dermatitis, pulmonaryconditions including asthma and chronic obstructive pulmonary disease(COPD), and other immune and inflammatory diseases including Crohndisease, ulcerative colitis, systemic lupus erythematosus, autoimmunechronic active hepatitis, osteoarthritis, tendonitis, and bursitis (J.Toogood, Glucocorticoids, N. J. Goulding and R. J. Flowers (eds.),Boston: Birkhauser, 2001, pp. 161-174). They have also been used to helpprevent rejection in organ transplantation.

Unfortunately, in addition to the desired therapeutic effects ofglucocorticoids, their use is associated with a number of adverse sideeffects, some of which can be severe and life-threatening. These includealterations in fluid and electrolyte balance, edema, weight gain,hypertension, muscle weakness, development or aggravation of diabetesmellitus, and osteoporosis. Therefore, a compound that exhibited areduced side effect profile while maintaining the potentanti-inflammatory effects would be particularly desirable, especiallywhen treating a chronic disease.

The effects of glucocorticoids are mediated at the cellular level by theglucocorticoid receptor (R. H. Oakley and J. Cidlowski, Glucocorticoids,N. J. Goulding and R. J. Flowers (eds.), Boston: Birkhauser, 2001, pp.55-80). The glucocorticoid receptor is a member of a class ofstructurally related intracellular receptors that when coupled with aligand can function as a transcription factor that affects geneexpression (R. M. Evans, Science, 1988, 240, pp. 889-895). Other membersof the family of steroid receptors include the mineralocorticoid,progesterone, estrogen, and androgen receptors. In addition to theeffects mentioned above for glucocorticoids, hormones that act on thisreceptor family have a profound influence on body homeostasis, mineralmetabolism, the stress response, and development of sexualcharacteristics. Glucocorticoids, N. J. Goulding and R. J. Flowers(eds.), Boston: Birkhauser, 2001, is hereby incorporated by reference inits entirety to better describe the state of the art.

A molecular mechanism which accounts for the beneficialanti-inflammatory effects and the undesired side effects has beenproposed (e.g., S. Heck et al., EMBO J. 1994, 17, pp. 4087-4095; H. M.Reichardt et al., Cell, 1998, 93, pp. 531-541; F. Tronche et al., Curr.Opin. in Genetics and Dev., 1998, 8, pp. 532-538). Many of the metabolicand cardiovascular side effects are thought to be the result of aprocess called transactivation. In transactivation, the translocation ofthe ligand-bound glucocorticoid receptor to the nucleus is followed bybinding to glucocorticoid response elements (GREs) in the promoterregion of side effect-associated genes, for example, phosphoenolpyruvatecarboxy kinase (PEPCK) in the case of increased glucose production. Theresult is an increased transcription rate of these genes which isbelieved to result, ultimately, in the observed side effects. Theanti-inflammatory effects are thought to be due to a process calledtransrepression. In general, transrepression is a process independent ofDNA binding that results from inhibition of NF-kB and AP-1-mediatedpathways, leading to down regulation of many inflammatory and immunemediators. Additionally, it is believed that a number of the observedside effects may be due to the cross-reactivity of the currentlyavailable glucocorticoids with other steroid receptors, particularly themineralocorticoid and progesterone receptors.

Thus, it may be possible to discover ligands for the glucocorticoidreceptor that are highly selective and, upon binding, can dissociate thetransactivation and transrepression pathways, providing therapeuticagents with a reduced side effect profile. Assay systems to determineeffects on transactivation and transrepression have been described(e.g., C. M. Bamberger and H. M. Schulte, Eur. J. Clin. Invest., 2000,30 (suppl. 3), pp. 6-9). Selectivity for the glucocorticoid receptor maybe determined by comparing the binding affinity for this receptor withthat of other steroid family receptors including those mentioned above.

Glucocorticoids also stimulate the production of glucose in the liver bya process called gluconeogenesis and it is believed that this process ismediated by transactivation events. Increased glucose production canexacerbate type II diabetes, therefore a compound that selectivityinhibited glucocorticoid mediated glucose production may havetherapeutic utility in this indication (J. E. Freidman et al., J. Biol.Chem., 1997, 272, pp. 31475-31481).

Novel ligands for the glucocorticoid receptor have been described in thescientific and patent literature. For example, PCT InternationalPublication No. WO 99/33786 discloses triphenylpropanamide compoundswith potential use in treating inflammatory diseases. PCT InternationalPublication No. WO 00/66522 describes non-steroidal compounds asselective modulators of the glucocorticoid receptor potentially usefulin treating metabolic and inflammatory diseases. PCT InternationalPublication No. WO 99/41256 describes tetracyclic modulators of theglucocorticoid receptor potentially useful in treating immune,autoimmune, and inflammatory diseases. U.S. Pat. No. 5,688,810 describesvarious non-steroidal compounds as modulators of glucocorticoid andother steroid receptors. PCT International Publication No. WO 99/63976describes a non-steroidal, liver-selective glucocorticoid antagonistpotentially useful in the treatment of diabetes. PCT InternationalPublication No. WO 00/32584 discloses non-steroidal compounds havinganti-inflammatory activity with dissociation between anti-inflammatoryand metabolic effects. PCT International Publication No. WO 98/54159describes non-steroidal cyclically substituted acylanilides with mixedgestagen and androgen activity. U.S. Pat. No. 4,880,839 describesacylanilides having progestational activity and EP 253503 disclosesacylanilides with antiandrogenic properties. PCT InternationalPublication No. WO 97/27852 describes amides that are inhibitors offarnesyl-protein transferase.

A compound that is found to interact with the glucocorticoid receptor ina binding assay could be an agonist or an antagonist. The agonistproperties of the compound could be evaluated in the transactivation ortransrepression assays described above. Given the efficacy demonstratedby available glucocorticoid drugs in inflammatory and immune diseasesand their adverse side effects, there remains a need for novelglucocorticoid receptor agonists with selectivity over other members ofthe steroid receptor family and a dissociation of the transactivationand transrepression activities. Alternatively, the compound may be foundto have antagonist activity. As mentioned above, glucocorticoidsstimulate glucose production in the liver. Increased glucose productioninduced by glucocorticoid excess can exacerbate existing diabetes, ortrigger latent diabetes. Thus a ligand for the glucocorticoid receptorthat is found to be an antagonist may be useful, inter alia, fortreating or preventing diabetes.

SUMMARY OF THE INVENTION

The instant invention is directed to compounds of Formula (I)

wherein:

-   R¹ is hydrogen or C₁-C₃ alkyl, each optionally independently    substituted with one to three substituent groups selected from    hydroxy, halogen, or oxo;-   R² is aryl optionally independently substituted with one to five    substituent groups,    -   wherein each substituent group of R² is independently C₁-C₅        alkyl, C₂-C₃ alkenyl, C₂-C₃ alkynyl, C₁-C₅ alkoxy, hydroxy,        nitro, trifluoromethyl, trifluoromethoxy, halogen, cyano,        acylamino, C₁-C₅ alkoxycarbonylamino, C₁-C₅ alkylsulfonylamino,        C₁-C₅ alkylthio, amino wherein the nitrogen atom is optionally        independently mono- or di-substituted by C₁-C₅ alkyl, or ureido        wherein either nitrogen atom is optionally independently        substituted with C₁-C₅ alkyl,        -   wherein each substituent group of R² is optionally            independently substituted with C₁-C₃ alkyl, halogen,            hydroxyl, or amino;-   R³ is C₁-C₈ alkyl independently substituted with one to five    substituent groups,    -   wherein each substituent group of R³ is independently C₃-C₆        cycloalkyl, aryl, halogen, trifluoromethyl, trifluoromethoxy, or        trifluoromethylthio and wherein at least one substituent is a        halogen;-   R⁴ is a hydrogen or C₁-C₅ alkyl, each optionally independently    substituted with one to three substituent groups,    -   wherein each substituent group of R⁴ is independently selected        from halogen, hydroxy, oxo, cyano, amino, or trifluoromethyl;-   R⁵ and R⁶ are each independently hydrogen, C₁-C₅ alkyl, or phenyl,    or R⁵ and R⁶ together with the carbon atom they are commonly    attached to form a C₃-C₈ spiro cycloalkyl ring, each optionally    independently substituted with one to three substituent groups,    -   wherein each substituent group of R⁵ and R⁶ is independently        selected from halogen, hydroxy, oxo, cyano, amino, or        trifluoromethyl; and-   R⁷ is a heteroaryl group optionally independently substituted with    one to three substituent groups,    -   wherein each substituent group of R⁷ is independently C₁-C₃        alkyl, C₂-C₅ alkenyl, C₂-C₅ alkynyl, heterocyclyl, aryl,        heteroaryl, C₁-C₅ alkoxy, aminocarbonyl, C₁-C₃        alkylaminocarbonyl, C₁-C₃ dialkylaminocarbonyl halogen, hydroxy,        carboxy, cyano, trifluoromethyl, trifluoromethoxy,        trifluoromethylthio, nitro, amino wherein the nitrogen atom is        optionally independently mono- or di-substituted by C₁-C₅ alkyl,        or C₁-C₅ alkylthio wherein the sulfur atom is optionally        oxidized to a sulfoxide or sulfone,        -   wherein each substituent group of R⁷ is optionally            independently substituted with one to three substituent            groups selected from C₁-C₃ alkyl, C₁-C₃ alkoxy, aryl, acyl,            acylamino, halogen, hydroxy, oxo, cyano, trifluoromethyl, or            amino wherein the nitrogen atom is optionally independently            mono- or di-substituted by C₁-C₅ alkyl,            or a tautomer, prodrug, solvate, or salt thereof.

One aspect of the invention includes compounds of Formula (I), wherein:

-   R¹ is hydrogen;-   R² is a phenyl or naphthyl group, each optionally independently    substituted with one to five substituent groups,    -   wherein each substituent group of R² is independently C₁-C₃        alkyl, C₁-C₅ alkoxy, hydroxy, nitro, trifluoromethyl,        trifluoromethoxy, halogen, cyano, C₁-C₅ alkylthio, or amino        wherein the nitrogen atom is optionally independently mono- or        di-substituted by C₁-C₅ alkyl;-   R³ is C₁-C₅ alkyl independently substituted with two to five    substituent groups, wherein each substituent group of R³ is C₃-C₈    cycloalkyl, halogen, trifluoromethyl, or trifluoromethoxy, and    wherein at least two substituents are halogens;-   R⁴ is hydrogen;-   R⁵ and R⁶ are each hydrogen or C₁-C₅ alkyl; and-   R⁷ is an indolyl, azaindolyl, diazaindolyl, imidazolyl,    dihydrobenzofuranyl, benzofuranyl, benzothienyl, benzimidazolyl,    isoquinolinyl, quinolinyl, tetrahydroquinolinyl,    tetrahydroquinoxalinyl, or pyridinyl group, each optionally    independently substituted with one to three substituent groups,    -   wherein each substituent group of R⁷ is independently C₁-C₃        alkyl, morpholinyl, piperdinyl, phenyl, pyridinyl, pyrimidinyl,        C₁-C₃ alkoxy, aminocarbonyl, C₁-C₃ alkylaminocarbonyl, C₁-C₃        dialkylaminocarbonyl, fluoro, chloro, bromo, cyano,        trifluoromethyl, or C₁-C₃ alkylthio wherein the sulfur atom is        optionally oxidized to a sulfoxide or sulfone,        -   wherein each substituent group of R⁷ is optionally            independently substituted with a substituent group selected            from methyl, methoxy, fluoro, chloro, bromo, oxo, or            trifluoromethyl,            or a tautomer, prodrug, solvate, or salt thereof.

Another aspect of the invention includes compounds of Formula (I),wherein:

-   R¹ is hydrogen;-   R² is a phenyl group,    -   wherein each substituent group of R² is independently C₁-C₅        alkyl, C₁-C₃ alkoxy, hydroxy, trifluoromethyl, trifluoromethoxy,        halogen, cyano, C₁-C₃ alkylthio, or amino wherein the nitrogen        atom is optionally independently mono- or di-substituted by        C₁-C₃ alkyl;-   R³ is trifluoromethyl, pentafluoroethyl, —CH₂CF₃, or —CF₂CH₃;-   R⁴ is hydrogen;-   R⁵ and R⁶ are each hydrogen; and-   R⁷ is an indolyl, azaindolyl, tetrahydroquinolinyl, or    tetrahydroquinoxalinyl group, each optionally independently    substituted with one to three substituent groups,    -   wherein each substituent group of R⁷ is independently C₁-C₃        alkyl, morpholinyl, piperdinyl, phenyl, pyridinyl, pyrimidinyl,        C₁-C₃ alkoxy, fluoro, chloro, bromo, cyano, trifluoromethyl, or        C₁-C₃ alkylthio wherein the sulfur atom is optionally oxidized        to a sulfoxide or sulfone,        -   wherein each substituent group of R⁷ is optionally            independently substituted with a substituent group selected            from methyl, methoxy, fluoro, chloro, bromo, oxo, or            trifluoromethyl,            or a tautomer, prodrug, solvate, or salt thereof.

The following are representative compounds of Formula (I) according tothe invention: Compound Name Compound Structure2,4,6-Trimethyl-N-[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]benzenesulfonamide

2,4,6-Trichloro-N-[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]benzenesulfonamide

2,4,6-Triisopropyl-N-[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]benzenesulfonamide

2-Amino-4,6-dichloro-N-[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]benzenesulfonamide

N-[2,2,2-Trifluoro-1-(1H-indol-3- ylmethyl)ethyl]benzenesulfonamide

2,4,6-Trimethyl-N-[2,2,2-trifluoro-1-(7-methyl-1H-indol-3-ylmethyl)ethyl]benzenesulfonamide

N-[1-(5-Cyano-1H-indol-3-ylmethyl)-2,2,2- trifluoroethyl]-2,4,6-trimethylbenzenesulfonamide

N-[1-(5-Bromo-1H-indol-3-ylmethyl)-2,2,2- trifluoroethyl]-2,4,6-trimethylbenzenesulfonamide

N-[1-(4-Bromo-1H-indol-3-ylmethyl)-2,2,2- trifluoroethyl]-2,4,6-trimethylbenzenesulfonamide

2,4,6-Trimethyl-N-[2,2,2-trifluoro-1-(1H- pyrrolo[3,2-b]pyridin-3-ylmethyl)ethyl]benzenesulfonamide

2,4,6-Trimethyl-N-[2,2,2-trifluoro-1-(4-methyl-1H-indol-3-ylmethyl)ethyl]benzenesulfonamide

2,4,6-Trimethyl-N-[2,2,2-trifluoro-1-(6-methyl-1H-indol-3-ylmethyl)ethyl]benzenesulfonamide

4-Bromo-2,6-dichloro-N-[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]benzenesulfonamide

2,4,6-Trimethyl-N-[2,2,2-trifluoro-1-(5-methyl-1H-indol-3-ylmethyl)ethyl]benzenesulfonamide

2-Amino-4,6-dichloro-N-[2,2,2-trifluoro-1-(5- methyl-1H-indol-3-ylmethyl)ethyl]benzenesulfonamide

Naphthalene-1-sulfonic acid [2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]amide

Naphthalene-2-sulfonic acid [2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]amide

5-Bromo-2-methoxy-N-[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]benzenesulfonamide

2-Methoxy-4-methyl-N-[2,2,2-trifluoro-1-(1H-indo1-3-ylmethyl)ethyl]benzenesulfonamide

2,4-Dichloro-6-methoxy-N-[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]benzenesulfonamide

2,4-Dichloro-6-hydroxy-N-[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]benzenesulfonamide

2-Amino-4,6-difluoro-N-[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]benzenesulfonamide

2-Amino-4,6-dimethyl-N-[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]benzenesulfonamide

2-Amino-4,6-dibromo-N-[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]benzenesulfonamide

2,4-Difluoro-6-hydroxy-N-[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]benzenesulfonamide

2-Hydroxy-4,6-dimethyl-N-[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]benzenesulfonamide

2,4-Dibromo-6-hydroxy-N-[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]benzenesulfonamide

2,4-Difluoro-6-methoxy-N-[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]benzenesulfonamide

2-Methoxy-4,6-dimethyl-N-[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]benzenesulfonamide

2,4-Dibromo-6-methoxy-N-[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]benzenesulfonamide

2-Amino-4,6-dichloro-N-[2,2,3,3,3-pentafluoro- 1-(1H-indol-3-ylmethyl)propyl]benzenesulfonamide

2-Amino-4,6-difluoro-N-[2,2,3,3,3-pentafluoro- 1-(1H-indol-3-ylmethyl)-propyl]benzenesulfonamide

2-Amino-4,6-dimethyl-N-[2,2,3,3,3-pentafluoro- 1-(1H-indol-3-ylmethyl)propyl]benzenesulfonamide

2-Amino-4,6-difluoro-N-[2,2,2-trifluoro-1-(5- methyl-1H-indol-3-ylmethyl)ethyl]benzenesulfonamide

2-Amino-4,6-dimethyl-N-[2,2,2-trifluoro-1-(5- methyl-1H-indol-3-ylmethyl)ethyl]benzenesulfonamide

2-Amino-4,6-dibromo-N-[2,2,2-trifluoro-1-(5- methyl-1H-indol-3-ylmethyl)ethyl]benzenesulfonamide

2,4-Dichloro-6-hydroxy-N-[2,2,2-trifluoro-1-(5- methyl-1H-indol-3-ylmethyl)ethyl]benzenesulfonamide

2-Amino-4,6-dichloro-N-[2,2,3,3,3-pentafluoro- 1-(5-methyl-1H-indol-3-ylmethyl)propyl]benzenesulfonamide

2-Amino-4,6-dichloro-N-[2,2,2-trifluoro-1-(1H- indol-3-ylmethyl)-1-methylethyl]benzenesulfonamide

2-Amino-4,6-dichloro-N-[1-(2,3-dihydroindol-1- ylmethyl)-2,2,2-trifluoroethyl]benzenesulfonamide

2-Amino-4,6-dichloro-N-(2,2,2-trifluoro-1-indol-1-ylmethylethyl)benzenesulfonamide

2-Amino-4,6-dichloro-N-[1-(2,3- dihydrobenzofuran-7-ylmethyl)-2,2,2-trifluoroethyl]benzenesulfonamide

2-Amino-4,6-dichloro-N-[1-(3,4-dihydro-2H-quinolin-1-ylmethyl)-2,2,2-trifluoroethyl]- benzenesulfonamide

2-Amino-4,6-dichloro-N-[2,2-difluoro-1-(1H-indol-3-ylmethyl)propyl]benzenesulfonamide

2-Amino-4,6-dichloro-N-[3,3,3-trifluoro-1-(1H-indol-3-ylmethyl)propyl]benzenesulfonamide

4-Amino-2,6-dichloro-N-[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]benzenesulfonamide

or a tautomer, prodrug, solvate, or salt thereof.

Preferred compounds of Formula (I) include the following:

-   2,4,6-Trimethyl-N-[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;-   2,4,6-Triisopropyl-N-[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]benzene    sulfonamide;-   2,4,6-Trimethyl-N-[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;-   2-Amino-4,6-dichloro-N-[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]benzene    sulfonamide;-   N-[2,2,2-Trifluoro-1-(1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;-   2,4,6-Trimethyl-N-[2,2,2-trifluoro-1-(7-methyl-1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;-   N-[1-(5-Cyano-1H-indol-3-ylmethyl)-2,2,2-trifluoroethyl]-2,4,6-trimethylbenzenesulfonamide;-   N-[1-(5-Bromo-1H-indol-3-ylmethyl)-2,2,2-trifluoroethyl]-2,4,6-trimethylbenzenesulfonamide;-   N-[1-(4-Bromo-1H-indol-3-ylmethyl)-2,2,2-trifluoroethyl]-2,4,6-trimethylbenzenesulfonamide;-   2,4,6-Trimethyl-N-[2,2,2-trifluoro-1-(1H-pyrrolo[3,2-b]pyridin-3-ylmethyl)ethyl]benzenesulfonamide;-   2,4,6-Trimethyl-N-[2,2,2-trifluoro-1-(4-methyl-1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;-   2,4,6-Trimethyl-N-[2,2,2-trifluoro-1-(6-methyl-1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;-   4-Bromo-2,6-dichloro-N-[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;-   2,4,6-Trimethyl-N-[2,2,2-trifluoro-1-(5-methyl-1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;-   2-Amino-4,6-dichloro-N-[2,2,2-trifluoro-1-(5-methyl-1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;-   Naphthalene-1-sulfonic acid    [2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]amide;-   Naphthalene-2-sulfonic acid    [2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]amide;-   5-Bromo-2-methoxy-N-[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;-   2-Methoxy-4-methyl-N-[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;-   2,4-Dichloro-6-methoxy-N-[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;    and-   2,4-Dichloro-6-hydroxy-N-[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]benzenesulfonamide,    or a tautomer, prodrug, solvate, or salt thereof.

More preferred compounds of Formula (I) include the following:

-   2,4,6-Trimethyl-N-[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;-   2,4,6-Triisopropyl-N-[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;-   2,4,6-Trimethyl-N-[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;-   2-Amino-4,6-dichloro-N-[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;-   2,4,6-Trimethyl-N-[2,2,2-trifluoro-1-(7-methyl-1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;-   N-[1-(5-Cyano-1H-indol-3-ylmethyl)-2,2,2-trifluoroethyl]-2,4,6-trimethylbenzenesulfonamide;-   N-[1-(5-Bromo-1H-indol-3-ylmethyl)-2,2,2-trifluoroethyl-2,4,6-trimethylbenzenesulfonamide;-   N-[1-(4-Bromo-1H-indol-3-ylmethyl)-2,2,2-trifluoroethyl]-2,4,6-trimethylbenzenesulfonamide;-   2,4,6-Trimethyl-N-[2,2,2-trifluoro-1-(1H-pyrrolo[3,2-b]pyridin-3-ylmethyl)ethyl]benzenesulfonamide;-   2,4,6-Trimethyl-N-[2,2,2-trifluoro-1-(4-methyl-1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;-   2,4,6-Trimethyl-N-[2,2,2-trifluoro-1-(6-methyl-1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;-   4-Bromo-2,6-dichloro-N-[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;-   2,4,6-Trimethyl-N-[2,2,2-trifluoro-1-(5-methyl-1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;-   2-Amino-4,6-dichloro-N-[2,2,2-trifluoro-1-(5-methyl-1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;-   Naphthalene-1-sulfonic acid    [2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]amide;-   Naphthalene-2-sulfonic acid    [2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]amide;-   2-Methoxy-4-methyl-N-[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;-   2,4-Dichloro-6-methoxy-N-[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;    and-   2,4-Dichloro-6-hydroxy-N-[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]benzenesulfonamide,    or a tautomer, prodrug, solvate, or salt thereof.

Most preferred compounds of Formula (I) include the following:

-   2,4,6-Trimethyl-N-[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;-   2,4,6-Triisopropyl-N-[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;-   2,4,6-Trimethyl-N-[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;-   2-Amino-4,6-dichloro-N-[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;-   2,4,6-Trimethyl-N-[2,2,2-trifluoro-1-(7-methyl-1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;-   N-[1-(5-Bromo-1H-indol-3-ylmethyl)-2,2,2-trifluoroethyl]-2,4,6-trimethylbenzenesulfonamide;-   N-[1-(4-Bromo-1H-indol-3-ylmethyl)-2,2,2-trifluoroethyl]-2,4,6-trimethylbenzenesulfonamide;-   2,4,6-Trimethyl-N-[2,2,2-trifluoro-1-(4-methyl-1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;-   2,4,6-Trimethyl-N-[2,2,2-trifluoro-1-(6-methyl-1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;-   4-Bromo-2,6-dichloro-N-[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;-   2,4,6-Trimethyl-N-[2,2,2-trifluoro-1-(5-methyl-1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;-   2-Amino-4,6-dichloro-N-[2,2,2-trifluoro-1-(5-methyl-1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;    and-   2,4-Dichloro-6-methoxy-N-[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]benzenesulfonamide,    or a tautomer, prodrug, solvate, or salt thereof.

The invention also provides a method of making a compound of Formula (I)

where R¹ is H and R², R³, R⁴, R⁵, R⁶, and R⁷ are as defined above, themethod comprising reacting an aziridine compound of Formula (II) with anorganometallic reagent R⁷-M of Formula (III) where M is Na, Li, or MgXand X is Cl, Br, or I, in a suitable solvent to form the compound ofFormula (I).

The invention further provides a method of making a compound of Formula(I)

where R¹, R⁴, R⁵, and R⁶ are each H, and R², R³, and R⁷ are as definedabove, the method

-   (a) reacting an epoxide of Formula (IV) with sodium azide in a    suitable solvent such as ethanol-water in the presence ammonium    chloride to provide an azide of Formula (V)-   (b) reducing the azide of Formula (V) with hydrogen in the presence    of a suitable catalyst such as palladium on carbon in a suitable    solvent such as methanol to form an amino alcohol of Formula (VI)-   (c) reacting the amino alcohol of Formula (VI) with a sulfonyl    chloride of Formula (VII) in a suitable solvent such as    tetrahydrofuran in the presence of a base such as sodium hydride or    in dichloromethane in the presence of pyridine followed by a    suitable base such as aqueous potassium hydroxide to form an    aziridine of Formula (VIII)-   (d) reacting the aziridine of Formula (VIII) with an organometallic    reagent R⁷-M of Formula (III) where M is Na, Li, or MgX and X is Cl,    Br, or I, in a suitable solvent such as ether, tetrahydrofuran, or    DMF to form the compound of Formula (I)

Alternatively, the group R² may be substituted with another R^(2′)group, the method comprising:

-   (a′) reacting a sulfonamide when R² is an ortho- or para-substituted    nitrophenyl with a thiol such as thiophenol in the presence of a    base such as potassium carbonate in DMF or, when R² is a    2,4,6-trimethyl-substituted phenyl, with magnesium metal in a    suitable solvent such as methanol under sonication to form an amine    of Formula (IX)-   (b′) reacting the aminoethyl compound of Formula (IX) with a    sulfonyl halide of Formula (VII) in the presence of a suitable base    to form the compound of Formula (I)

Another method for making a compound of Formula (I) comprises:

-   (a) reacting a bromoketone of Formula (X) with hydroxylamine    hydrochloride in chloroform-water or ethanol-water to form an oxime    of Formula (XI)-   (b) reacting the oxime of Formula (XI) with an indole or azaindole    (where R⁷ is indole) of Formula (XII) in the presence of a suitable    base in a suitable solvent such as dichloromethane or tert-butyl    methyl ether to form the intermediate of Formula (XIII)-   (c) reducing the oxime of Formula (XIII) with a suitable reducing    agent such a lithium aluminum hydride in a suitable solvent such as    ether or THF to form a compound of Formula (XIV)-   (d) reacting the intermediate of Formula (XIV) with a sulfonyl    halide of Formula (VII) in the presence of a suitable base to form    the compound of Formula (I)

In another aspect of the invention, the compounds according to theinvention are formulated into pharmaceutical compositions comprising aneffective amount, preferably a pharmaceutically effective amount, of acompound according to the invention or a tautomer, prodrug, solvate, orsalt thereof, and a pharmaceutically acceptable excipient or carrier.

The invention also provides a method of modulating the glucocorticoidreceptor function in a patient, the method comprising administering tothe patient an effective amount of a compound according to the inventionor a tautomer, prodrug, solvate, or salt thereof.

The invention further provides a method of treating a disease-state orcondition mediated by the glucocorticoid receptor function in a patientin need of such treatment, the method comprising administering to thepatient an effective amount of a pharmaceutically acceptable compoundaccording to the invention or a tautomer, prodrug, solvate, or saltthereof.

In addition, the invention also provides a method of treating adisease-state or condition selected from: type II diabetes, obesity,cardiovascular diseases, hypertension, arteriosclerosis, neurologicaldiseases, adrenal and pituitary tumors, and glaucoma, in a patient inneed of such treatment, the method comprising administering to thepatient an effective amount of a pharmaceutically acceptable compoundaccording to the invention or a tautomer, prodrug, solvate, or saltthereof.

The invention provides a method of treating a disease characterized byinflammatory, allergic, or proliferative processes, in a patient in needof such treatment, the method comprising administering to the patient aneffective amount of a pharmaceutically acceptable compound according tothe invention or a tautomer, prodrug, solvate, or salt thereof. In apreferred embodiment of the invention, the disease characterized byinflammatory, allergic, or proliferative processes is selected from: (i)lung diseases; (ii) rheumatic diseases or autoimmune diseases or jointdiseases; (iii) allergic diseases; (iv) vasculitis diseases; (v)dermatological diseases; (vi) renal diseases; (vii) hepatic diseases;(viii) gastrointestinal diseases; (ix) proctological diseases; (x) eyediseases; (xi) diseases of the ear, nose, and throat (ENT) area; (xii)neurological diseases; (xiii) blood diseases; (xiv) tumor diseases; (xv)endocrine diseases; (xvi) organ and tissue transplantations andgraft-versus-host diseases; (xvii) severe states of shock; (xviii)substitution therapy; and (xix) pain of inflammatory genesis. In anotherpreferred embodiment of the invention, the disease characterized byinflammatory, allergic, or proliferative processes is selected from:type I diabetes, osteoarthritis, Guillain-Barre syndrome, restenosisfollowing percutaneous transluminal coronary angioplasty, Alzheimerdisease, acute and chronic pain, atherosclerosis, reperfusion injury,bone resorption diseases, congestive heart failure, myocardialinfarction, thermal injury, multiple organ injury secondary to trauma,acute purulent meningitis, necrotizing enterocolitis, and syndromesassociated with hemodialysis, leukopheresis, and granulocytetransfusion.

The invention further provides methods of treating the disease-states orconditions mentioned above, in a patient in need of such treatment, themethods comprising sequentially or simultaneously administering to thepatient: (a) an effective amount of a pharmaceutically acceptablecompound according to the invention or a tautomer, prodrug, solvate, orsalt thereof; and (b) a pharmaceutically acceptable glucocorticoid.

The invention further provides a method of assaying the glucocorticoidreceptor function in a sample, comprising: (a) contacting the samplewith a selected amount of a compound according to the invention or atautomer, prodrug, solvate, or salt thereof; and (b) detecting theamount of the compound according to the invention or a tautomer,prodrug, solvate, or salt thereof bound to glucocorticoid receptors inthe sample. In a preferred embodiment of the invention, the compoundaccording to the invention or a tautomer, prodrug, solvate, or saltthereof is labeled with a detectable marker selected from: a radiolabel,fluorescent tag, a chemiluminescent tag, a chromophore, and a spinlabel.

The invention also provides a method of imaging the glucocorticoidreceptor distribution in a sample or patient, the method comprising: (a)contacting the sample or administering to a patient a compound accordingto the invention or a tautomer, prodrug, solvate, or salt thereof havinga detectable marker; (b) detecting the spatial distribution and amountof the compound according to the invention or a tautomer, prodrug,solvate, or salt thereof having a detectable marker bound toglucocorticoid receptors in the sample or patient using an imaging meansto obtain an image; and (c) displaying an image of the spatialdistribution and amount of the compound according to the invention or atautomer, prodrug, solvate, or salt thereof having a detectable markerbound to glucocorticoid receptors in the sample. In a preferredembodiment of the invention, the imaging means is selected from:radioscintigraphy, nuclear magnetic resonance imaging (MRI), computedtomography (CT scan), or positron emission tomography (PET).

The invention also provides a kit for the in vitro diagnosticdetermination of the glucocorticoid receptor function in a sample,comprising: (a) a diagnostically effective amount of a compoundaccording to the invention or a tautomer, prodrug, solvate, or saltthereof; and (b) instructions for use of the diagnostic kit.

Definition of Terms and Conventions Used

Terms not specifically defined herein should be given the meanings thatwould be given to them by one of skill in the art in light of thedisclosure and the context. As used in the specification and appendedclaims, however, unless specified to the contrary, the following termshave the meaning indicated and the following conventions are adhered to.

A. Chemical Nomenclature, Terms, and Conventions

In the groups, radicals, or moieties defined below, the number of carbonatoms is often specified preceding the group, for example, C₁-C₁₀ alkylmeans an alkyl group or radical having 1 to 10 carbon atoms. The term“lower” applied to any carbon-containing group means a group containingfrom 1 to 8 carbon atoms, as appropriate to the group (i.e., a cyclicgroup must have at least 3 atoms to constitute a ring). In general, forgroups comprising two or more subgroups, the last named group is theradical attachment point, for example, “alkylaryl” means a monovalentradical of the formula Alk-Ar—, while “arylalkyl” means a monovalentradical of the formula Ar-Alk- (where Alk is an alkyl group and Ar is anaryl group). Furthermore, the use of a term designating a monovalentradical where a divalent radical is appropriate shall be construed todesignate the respective divalent radical and vice versa. Unlessotherwise specified, conventional definitions of terms control andconventional stable atom valences are presumed and achieved in allformulas and groups. The terms “alkyl” or “alkyl group” mean a branchedor straight-chain saturated aliphatic hydrocarbon monovalent radical.This term is exemplified by groups such as methyl, ethyl, n-propyl,1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1-dimethylethyl(tert-butyl), and the like. It may be abbreviated “Alk”.

The terms “alkenyl” or “alkenyl group” mean a branched or straight-chainaliphatic hydrocarbon monovalent radical containing at least onecarbon-carbon double bond. This term is exemplified by groups such asethenyl, propenyl, n-butenyl, isobutenyl, 3-methylbut-2-enyl,n-pentenyl, heptenyl, octenyl, decenyl, and the like.

The terms “alkynyl” or “alkynyl group” mean a branched or straight-chainaliphatic hydrocarbon monovalent radical containing at least onecarbon-carbon triple bond. This term is exemplified by groups such asethynyl, propynyl, n-butynyl, 2-butynyl, 3-methylbutynyl, n-pentynyl,heptynyl, octynyl, decynyl, and the like.

The terms “alkylene” or “alkylene group” mean a branched orstraight-chain saturated aliphatic hydrocarbon divalent radical havingthe specified number of carbon atoms. This term is exemplified by groupssuch as methylene, ethylene, propylene, n-butylene, and the like, andmay alternatively and equivalently be denoted herein as -(alkyl)-.

The terms “alkenylene” or “alkenylene group” mean a branched orstraight-chain aliphatic hydrocarbon divalent radical having thespecified number of carbon atoms and at least one carbon-carbon doublebond. This term is exemplified by groups such as ethenylene,propenylene, n-butenylene, and the like, and may alternatively andequivalently be denoted herein as -(alkylenyl)-.

The terms “alkynylene” or “alkynylene group” mean a branched orstraight-chain aliphatic hydrocarbon divalent radical containing atleast one carbon-carbon triple bond. This term is exemplified by groupssuch as ethynylene, propynylene, n-butynylene, 2-butynylene,3-methylbutynylene, n-pentynylene, heptynylene, octynylene, decynylene,and the like, and may alternatively and equivalently be denoted hereinas -(alkynyl)-.

The terms “alkoxy” or “alkoxy group” mean a monovalent radical of theformula AlkO—, where Alk is an alkyl group. This term is exemplified bygroups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy,tert-butoxy, pentoxy, and the like.

The terms “aryloxy”, “aryloxy group”, mean a monovalent radical of theformula ArO—, where Ar is aryl. This term is exemplified by groups suchas phenoxy, naphthoxy, and the like.

The terms “alkylcarbonyl”, “alkylcarbonyl group”, “alkanoyl”, or“alkanoyl group” mean a monovalent radical of the formula AlkC(O)—,where Alk is alkyl or hydrogen.

The terms “arylcarbonyl”, “arylcarbonyl group”, “aroyl” or “aroyl group”mean a monovalent radical of the formula ArC(O)—, where Ar is aryl.

The terms “acyl” or “acyl group” mean a monovalent radical of theformula RC(O)—, where R is a substituent selected from hydrogen or anorganic substituent. Exemplary substituents include alkyl, aryl,arylalkyl, cycloalkyl, heterocyclyl, heteroaryl, heteroarylalkyl, andthe like. As such, the terms comprise alkylcarbonyl groups andarylcarbonyl groups.

The terms “acylamino” or “acylamino group” mean a monovalent radical ofthe formula RC(O)N(R)—, where each R is a substituent selected fromhydrogen or a substituent group.

The terms “alkoxycarbonyl” or “alkoxycarbonyl group” mean a monovalentradical of the formula AlkO—C(O)—, where Alk is alkyl. Exemplaryalkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl,tert-butyloxycarbonyl, and the like.

The terms “aryloxycarbonyl” or “aryloxycarbonyl group” mean a monovalentradical of the formula ArO—C(O)—, where Ar is aryl.

The terms “alkylcarbonyloxy” or “alkylcarbonyloxy group” or“alkanoyloxy” or “alkanoyloxy group” mean a monovalent radical of theformula AlkC(O)O—, where Alk is alkyl.

The terms “arylcarbonyloxy” or “arylcarbonyloxy group” or “aroyloxy” or“aroyloxy group” mean a monovalent radical of the formula ArC(O)O—,where Ar is aryl.

The terms “alkylaminocarbonyloxy” or “alkylaminocarbonyloxy group” meana monovalent radical of the formula R₂NC(O)O—, where each R isindependently hydrogen or lower alkyl.

The term “alkoxycarbonylamino” or “alkoxycarbonylamino group” mean amonovalent radical of the formula ROC(O)NH—, where R is lower alkyl.

The terms “alkylcarbonylamino” or “alkylcarbonylamino group” or“alkanoylamino” or “alkanoylamino groups” mean a monovalent radical ofthe formula AlkC(O)NH—, where Alk is alkyl. Exemplary alkylcarbonylaminogroups include acetamido (CH₃C(O)NH—).

The terms “alkylaminocarbonyloxy” or “alkylaminocarbonyloxy group” meana monovalent radical of the formula AlkNHC(O)O—, where Alk is alkyl.

The terms “amino” or “amino group” mean an —NH₂ group.

The terms “alkylamino” or “alkylamino group” mean a monovalent radicalof the formula (Alk)NH—, where Alk is alkyl. Exemplary alkylamino groupsinclude methylamino, ethylamino, propylamino, butylamino,tert-butylamino, and the like.

The terms “dialkylamino” or “dialkylamino group” mean a monovalentradical of the formula (Alk)(Alk)N—, where each Alk is independentlyalkyl. Exemplary dialkylamino groups include dimethylamino,methylethylamino, diethylamino, dipropylamino, ethylpropylamino, and thelike.

The terms “substituted amino” or “substituted amino group” mean amonovalent radical of the formula —NR₂, where each R is independently asubstituent selected from hydrogen or the specified substituents (butwhere both Rs cannot be hydrogen). Exemplary substituents include alkyl,alkanoyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heteroaryl,heteroarylalkyl, and the like.

The terms “alkoxycarbonylamino” or “alkoxycarbonylamino group” mean amonovalent radical of the formula AlkOC(O)NH—, where Alk is alkyl.

The terms “ureido” or “ureido group” mean a monovalent radical of theformula R₂NC(O)NH—, where each R is independently hydrogen or alkyl.

The terms “halogen” or “halogen group” mean a fluoro, chloro, bromo, oriodo group.

The term “halo” means one or more hydrogen atoms of the group arereplaced by halogen groups.

The terms “haloalkyl” or “haloalkyl group” mean a branched orstraight-chain saturated aliphatic hydrocarbon monovalent radical,wherein one or more hydrogen atoms thereof are each independentlyreplaced with halogen atoms. This term is exemplified by groups such aschloromethyl, 1,2-dibromoethyl, 1,1,1-trifluoropropyl, 2-iodobutyl,1-chloro-2-bromo-3-fluoropentyl, and the like.

The terms “sulfanyl”, “sulfanyl group”, “thioether”, or “thioethergroup” mean a divalent radical of the formula —S—.

The terms “alkylthio” or “alkylthio group” mean a monovalent radical ofthe formula AlkS—, where Alk is alkyl. Exemplary groups includemethylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, and thelike.

The terms “arylthio” or “arylthio group” mean a monovalent radical ofthe formula ArS—, where Ar is aryl.

The terms “sulfinyl”, “sulfinyl group”, “thionyl”, or “thionyl group”mean a divalent radical of the formula —SO—.

The terms “sulfonyl” or “sulfonyl group” mean a divalent radical of theformula —SO₂—.

The terms “sulfonylamino” or “sulfonylamino group” mean a divalentradical of the formula —SO₂NR—, where R is a hydrogen or a substituentgroup.

The terms “aminosulfonyl” or “aminosulfonyl group” mean a monovalentradical of the formula NR₂SO₂—, where R is each independently a hydrogenor a substituent group.

The terms “carbocycle” or “carbocyclic group” mean a stable aliphatic 3-to 15-membered monocyclic or polycyclic monovalent or divalent radicalconsisting solely of carbon and hydrogen atoms which may comprise one ormore fused or bridged ring(s), preferably a 5- to 7-membered monocyclicor 7- to 10-membered bicyclic ring. Unless otherwise specified, thecarbocycle may be attached at any carbon atom which results in a stablestructure and, if substituted, may be substituted at any suitable carbonatom which results in a stable structure. The term comprises cycloalkyl(including spiro cycloalkyl), cycloalkylene, cycloalkenyl,cycloalkenylene, cycloalkynyl, and cycloalkynylene, and the like.

The terms “cycloalkyl” or “cycloalkyl group” mean a stable aliphaticsaturated 3- to 15-membered monocyclic or polycyclic monovalent radicalconsisting solely of carbon and hydrogen atoms which may comprise one ormore fused or bridged ring(s), preferably a 5- to 7-membered monocyclicor 7- to 10-membered bicyclic ring. Unless otherwise specified, thecycloalkyl ring may be attached at any carbon atom which results in astable structure and, if substituted, may be substituted at any suitablecarbon atom which results in a stable structure. Exemplary cycloalkylgroups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornane, adamantyl,tetrahydronaphthyl (tetralin), 1-decalinyl, bicyclo[2.2.2]octanyl,1-methylcyclopropyl, 2-methylcyclopentyl, 2-methylcyclooctyl, and thelike.

The terms “cycloalkenyl” or “cycloalkenyl group” mean a stable aliphatic5- to 15-membered monocyclic or polycyclic monovalent radical having atleast one carbon-carbon double bond and consisting solely of carbon andhydrogen atoms which may comprise one or more fused or bridged ring(s),preferably a 5- to 7-membered monocyclic or 7- to 10-membered bicyclicring. Unless otherwise specified, the cycloalkenyl ring may be attachedat any carbon atom which results in a stable structure and, ifsubstituted, may be substituted at any suitable carbon atom whichresults in a stable structure. Exemplary cycloalkenyl groups includecyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl,cyclodecenyl, norbornenyl, 2-methylcyclopentenyl, 2-methylcyclooctenyl,and the like.

The terms “cycloalkynyl” or “cycloalkynyl group” mean a stable aliphatic8- to 15-membered monocyclic or polycyclic monovalent radical having atleast one carbon-carbon triple bond and consisting solely of carbon andhydrogen atoms which may comprise one or more fused or bridged ring(s),preferably a 8- to 10-membered monocyclic or 12- to 15-membered bicyclicring. Unless otherwise specified, the cycloalkynyl ring may be attachedat any carbon atom which results in a stable structure and, ifsubstituted, may be substituted at any suitable carbon atom whichresults in a stable structure. Exemplary cycloalkynyl groups include,cyclooctynyl, cyclononynyl, cyclodecynyl, 2-methylcyclooctynyl, and thelike.

The terms “cycloalkylene” or “cycloalkylene group” mean a stablesaturated aliphatic 3- to 15-membered monocyclic or polycyclic divalentradical consisting solely of carbon and hydrogen atoms which maycomprise one or more fused or bridged ring(s), preferably a 5- to7-membered monocyclic or 7- to 10-membered bicyclic ring. Unlessotherwise specified, the cycloalkyl ring may be attached at any carbonatom which results in a stable structure and, if substituted, may besubstituted at any suitable carbon atom which results in a stablestructure. Exemplary cycloalkylene groups include cyclopentylene, andthe like.

The terms “cycloalkenylene” or “cycloalkenylene group” mean a stablealiphatic 5- to 15-membered monocyclic or polycyclic divalent radicalhaving at least one carbon-carbon double bond and consisting solely ofcarbon and hydrogen atoms which may comprise one or more fused orbridged ring(s), preferably a 5- to 7-membered monocyclic or 7- to10-membered bicyclic ring. Unless otherwise specified, thecycloalkenylene ring may be attached at any carbon atom which results ina stable structure and, if substituted, may be substituted at anysuitable carbon atom which results in a stable structure. Exemplarycycloalkenylene groups include cyclopentenylene, cyclohexenylene,cycloheptenylene, cyclooctenylene, cyclononenylene, cyclodecenylene,norbornenylene, 2-methylcyclopentenylene, 2-methylcyclooctenylene, andthe like.

The terms “cycloalkynylene” or “cycloalkynylene group” mean a stablealiphatic 8- to 15-membered monocyclic or polycyclic divalent radicalhaving at least one carbon-carbon triple bond and consisting solely ofcarbon and hydrogen atoms which may comprise one or more fused orbridged ring(s), preferably a 8- to 10-membered monocyclic or 12- to15-membered bicyclic ring. Unless otherwise specified, thecycloalkynylene ring may be attached at any carbon atom which results ina stable structure and, if substituted, may be substituted at anysuitable carbon atom which results in a stable structure. Exemplarycycloalkynylene groups include cyclooctynylene, cyclononynylene,cyclodecynylene, 2-methylcyclooctynylene, and the like.

The terms “aryl” or “aryl group” mean an aromatic carbocyclic monovalentor divalent radical of from 6 to 14 carbon atoms having a single ring(e.g., phenyl or phenylene) or multiple condensed rings (e.g., naphthylor anthranyl). Unless otherwise specified, the aryl ring may be attachedat any suitable carbon atom which results in a stable structure and, ifsubstituted, may be substituted at any suitable carbon atom whichresults in a stable structure. Exemplary aryl groups include phenyl,naphthyl, anthryl, phenanthryl, indanyl, indenyl, biphenyl, and thelike. It may be abbreviated “Ar”.

The terms “heteroaryl” or “heteroaryl group” mean a stable aromatic 5-to 14-membered, monocyclic or polycyclic monovalent or divalent radicalwhich may comprise one or more fused or bridged ring(s), preferably a 5-to 7-membered monocyclic or 7- to 10-membered bicyclic radical, havingfrom one to four heteroatoms in the ring(s) independently selected fromnitrogen, oxygen, and sulfur, wherein any sulfur heteroatoms mayoptionally be oxidized and any nitrogen heteroatom may optionally beoxidized or be quaternized. Unless otherwise specified, the heteroarylring may be attached at any suitable heteroatom or carbon atom whichresults in a stable structure and, if substituted, may be substituted atany suitable heteroatom or carbon atom which results in a stablestructure. Exemplary and preferred heteroaryls include furanyl, thienyl,pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl,isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl,pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, indolyl,azaindolyl, dihydroindolyl, isoindolyl, benzofuranyl,dihydrobenzofuranyl, benzothienyl, dihydrobenzothienyl, indazolyl,benzimidazolyl, benzthiazolyl, benzoxazolyl, benzisoxazolyl,benzpyrazolyl, purinyl, quinolizinyl, quinolinyl, dihydroquinolinyl,tetrahydroquinolinyl, tetrahydroquinoxalinyl, isoquinolinyl,dihydroisoquinolinyl, tetrahydroisoquinolinyl, cinnolinyl, phthalazinyl,quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl,acridinyl, phenazinyl, phenothiazinyl, and phenoxazinyl, and the like.

The terms “heterocycle”, “heterocycle group”, “heterocyclyl”, or“heterocyclyl group” mean a stable non-aromatic 5- to 14-memberedmonocyclic or polycyclic, monovalent or divalent, ring which maycomprise one or more fused or bridged ring(s), preferably a 5- to7-membered monocyclic or 7- to 10-membered bicyclic ring, having fromone to three heteroatoms in the ring(s) independently selected fromnitrogen, oxygen, and sulfur, wherein any sulfur heteroatoms mayoptionally be oxidized and any nitrogen heteroatom may optionally beoxidized or be quaternized. Unless otherwise specified, the heterocyclylring may be attached at any suitable heteroatom or carbon atom whichresults in a stable structure and, if substituted, may be substituted atany suitable heteroatom or carbon atom which results in a stablestructure. Exemplary and preferred heterocycles include pyrrolinyl,pyrrolidinyl, pyrazolinyl, pyrazolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, tetrahydropyranyl, tetrahydrothiopyranyl,tetrahydrofuranyl, hexahydropyrimidinyl, hexahydropyridazinyl, and thelike.

The term “compounds of the invention” and equivalent expressions aremeant to embrace compounds of Formula (I) as herein described, includingthe tautomers, the prodrugs, the salts, particularly thepharmaceutically acceptable salts, and the solvates and hydratesthereof, where the context so permits. In general and preferably, thecompounds of the invention and the formulas designating the compounds ofthe invention are understood to only include the stable compoundsthereof and exclude unstable compounds, even if an unstable compoundmight be considered to be literally embraced by the compound formula.Similarly, reference to intermediates, whether or not they themselvesare claimed, is meant to embrace their salts and solvates, where thecontext so permits. For the sake of clarity, particular instances whenthe context so permits are sometimes indicated in the text, but theseinstances are purely illustrative and it is not intended to excludeother instances when the context so permits.

The terms “optional” or “optionally” mean that the subsequentlydescribed event or circumstances may or may not occur, and that thedescription includes instances where the event or circumstance occursand instances in which it does not. For example, “optionally substitutedaryl” means that the aryl radical may or may not be substituted and thatthe description includes both substituted aryl radicals and arylradicals having no substitution.

The terms “stable compound” or “stable structure” mean a compound thatis sufficiently robust to survive isolation to a useful degree of purityfrom a reaction mixture, and formulation into an efficacious therapeuticor diagnostic agent. For example, a compound which would have a“dangling valency” or is a carbanion is not a compound contemplated bythe invention.

The term “substituted” means that any one or more hydrogens on an atomof a group or moiety, whether specifically designated or not, isreplaced with a selection from the indicated group of substituents,provided that the atom's normal valency is not exceeded and that thesubstitution results in a stable compound. If a bond to a substituent isshown to cross the bond connecting two atoms in a ring, then suchsubstituent may be bonded to any atom on the ring. When a substituent islisted without indicating the atom via which such substituent is bondedto the rest of the compound, then such substituent may be bonded via anyatom in such substituent. For example, when the substituent ispiperazinyl, piperidinyl, or tetrazolyl, unless specified otherwise,such piperazinyl, piperidinyl, or tetrazolyl group may be bonded to therest of the compound of the invention via any atom in such piperazinyl,piperidinyl, or tetrazolyl group. Generally, when any substituent orgroup occurs more than one time in any constituent or compound, itsdefinition on each occurrence is independent of its definition at everyother occurrence. Thus, for example, if a group is shown to besubstituted with 0 to 2 R⁵, then such group is optionally substitutedwith up to two R⁵ groups and R⁵ at each occurrence is selectedindependently from the defined list of possible R⁵. Such combinations ofsubstituents and/or variables, however, are permissible only if suchcombinations result in stable compounds.

In a specific embodiment, the term “about” or “approximately” meanswithin 20%, preferably within 10%, and more preferably within 5% of agiven value or range.

The yield of each of the reactions described herein is expressed as apercentage of the theoretical yield.

B. Salt, Prodrug, Derivative, and Solvate Terms and Conventions

The terms “prodrug” or “prodrug derivative” mean a covalently-bondedderivative or carrier of the parent compound or active drug substancewhich undergoes at least some biotransformation prior to exhibiting itspharmacological effect(s). In general, such prodrugs have metabolicallycleavable groups and are rapidly transformed in vivo to yield the parentcompound, for example, by hydrolysis in blood, and generally includeesters and amide analogs of the parent compounds. The prodrug isformulated with the objectives of improved chemical stability, improvedpatient acceptance and compliance, improved bioavailability, prolongedduration of action, improved organ selectivity, improved formulation(e.g., increased hydrosolubility), and/or decreased side effects (e.g.,toxicity). In general, prodrugs themselves have weak or no biologicalactivity and are stable under ordinary conditions. Prodrugs can bereadily prepared from the parent compounds using methods known in theart, such as those described in A Textbook of Drug Design andDevelopment, Krogsgaard-Larsen and H. Bundgaard (eds.), Gordon & Breach,1991, particularly Chapter 5: “Design and Applications of Prodrugs”;Design of Prodrugs, H. Bundgaard (ed.), Elsevier, 1985; Prodrugs:Topical and Ocular Drug Delivery, K. B. Sloan (ed.), Marcel Dekker,1998; Methods in Enzymology, K. Widder et al. (eds.), Vol. 42, AcademicPress, 1985, particularly pp. 309-396; Burger's Medicinal Chemistry andDrug Discovery, 5th Ed., M. Wolff (ed.), John Wiley & Sons, 1995,particularly Vol. 1 and pp. 172-178 and pp. 949-982; Pro-Drugs as NovelDelivery Systems, T. Higuchi and V. Stella (eds.), Am. Chem. Soc., 1975;and Bioreversible Carriers in Drug Design, E. B. Roche (ed.), Elsevier,1987, each of which is incorporated herein by reference in theirentireties.

The term “pharmaceutically acceptable prodrug” as used herein means aprodrug of a compound of the invention which is, within the scope ofsound medical judgment, suitable for use in contact with the tissues ofhumans and lower animals without undue toxicity, irritation, allergicresponse, and the like, commensurate with a reasonable benefit/riskratio, and effective for their intended use, as well as the zwitterionicforms, where possible.

The term “salt” means an ionic form of the parent compound or theproduct of the reaction between the parent compound with a suitable acidor base to make the acid salt or base salt of the parent compound. Saltsof the compounds of the present invention can be synthesized from theparent compounds which contain a basic or acidic moiety by conventionalchemical methods. Generally, the salts are prepared by reacting the freebase or acid parent compound with stoichiometric amounts or with anexcess of the desired salt-forming inorganic or organic acid or base ina suitable solvent or various combinations of solvents.

The term “pharmaceutically acceptable salt” means a salt of a compoundof the invention which is, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response, and the like,commensurate with a reasonable benefit/risk ratio, generally water oroil-soluble or dispersible, and effective for their intended use. Theterm includes pharmaceutically-acceptable acid addition salts andpharmaceutically-acceptable base addition salts. As the compounds of thepresent invention are useful in both free base and salt form, inpractice, the use of the salt form amounts to use of the base form.Lists of suitable salts are found in, e.g., S. M. Birge et al., J.Pharm. Sci., 1977, 66, pp. 1-19, which is hereby incorporated byreference in its entirety.

The term “pharmaceutically-acceptable acid addition salt” means thosesalts which retain the biological effectiveness and properties of thefree bases and which are not biologically or otherwise undesirable,formed with inorganic acids such as hydrochloric acid, hydrobromic acid,hydroiodic acid, sulfuric acid, sulfamic acid, nitric acid, phosphoricacid, and the like, and organic acids such as acetic acid,trichloroacetic acid, trifluoroacetic acid, adipic acid, alginic acid,ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid,2-acetoxybenzoic acid, butyric acid, camphoric acid, camphorsulfonicacid, cinnamic acid, citric acid, digluconic acid, ethanesulfonic acid,glutamic acid, glycolic acid, glycerophosphoric acid, hemisulfic acid,heptanoic acid, hexanoic acid, formic acid, fumaric acid,2-hydroxyethanesulfonic acid (isethionic acid), lactic acid, maleicacid, hydroxymaleic acid, malic acid, malonic acid, mandelic acid,mesitylenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid,nicotinic acid, 2-naphthalenesulfonic acid, oxalic acid, pamoic acid,pectinic acid, phenylacetic acid, 3-phenylpropionic acid, picric acid,pivalic acid, propionic acid, pyruvic acid, pyruvic acid, salicylicacid, stearic acid, succinic acid, sulfanilic acid, tartaric acid,p-toluenesulfonic acid, undecanoic acid, and the like.

The term “pharmaceutically-acceptable base addition salt” means thosesalts which retain the biological effectiveness and properties of thefree acids and which are not biologically or otherwise undesirable,formed with inorganic bases such as ammonia or hydroxide, carbonate, orbicarbonate of ammonium or a metal cation such as sodium, potassium,lithium, calcium, magnesium, iron, zinc, copper, manganese, aluminum,and the like. Particularly preferred are the ammonium, potassium,sodium, calcium, and magnesium salts. Salts derived frompharmaceutically-acceptable organic nontoxic bases include salts ofprimary, secondary, and tertiary amines, quaternary amine compounds,substituted amines including naturally occurring substituted amines,cyclic amines and basic ion-exchange resins, such as methylamine,dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine,isopropylamine, tripropylamine, tributylamine, ethanolamine,diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol,dicyclohexylamine, lysine, arginine, histidine, caffeine, hydrabamine,choline, betaine, ethylenediamine, glucosamine, methylglucamine,theobromine, purines, piperazine, piperidine, N-ethylpiperidine,tetramethylammonium compounds, tetraethylammonium compounds, pyridine,N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine,dicyclohexylamine, dibenzylamine, N,N-dibenzylphenethylamine,1-ephenamine, N,N′-dibenzylethylenediamine, polyamine resins, and thelike. Particularly preferred organic nontoxic bases are isopropylamine,diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline,and caffeine.

The term “solvate” means a physical association of a compound with oneor more solvent molecules or a complex of variable stoichiometry formedby a solute (for example, a compound of Formula (I)) and a solvent, forexample, water, ethanol, or acetic acid. This physical association mayinvolve varying degrees of ionic and covalent bonding, includinghydrogen bonding. In certain instances, the solvate will be capable ofisolation, for example, when one or more solvent molecules areincorporated in the crystal lattice of the crystalline solid. Ingeneral, the solvents selected do not interfere with the biologicalactivity of the solute. Solvates encompasses both solution-phase andisolatable solvates. Representative solvates include hydrates,ethanolates, methanolates, and the like.

The term “hydrate” means a solvate wherein the solvent molecule(s)is/are H₂O.

The compounds of the present invention as discussed below include thefree base or acid thereof, their salts, solvates, and prodrugs and mayinclude oxidized sulfur atoms or quaternized nitrogen atoms in theirstructure, although not explicitly stated or shown, particularly thepharmaceutically acceptable forms thereof. Such forms, particularly thepharmaceutically acceptable forms, are intended to be embraced by theappended claims.

C. Isomer Terms and Conventions

The term “isomers” means compounds having the same number and kind ofatoms, and hence the same molecular weight, but differing with respectto the arrangement or configuration of their atoms in space. The termincludes stereoisomers and geometric isomers.

The terms “stereoisomer” or “optical isomer” means a stable isomer thathas at least one chiral atom or restricted rotation giving rise toperpendicular dissymmetric planes (e.g., certain biphenyls, allenes, andspiro compounds) and can rotate plane-polarized light. Becauseasymmetric centers and other chemical structure exist in the compoundsof the invention which may give rise to stereoisomerism, the inventioncontemplates stereoisomers and mixtures thereof. The compounds of theinvention and their salts include asymmetric carbon atoms and maytherefore exist as single stereoisomers, racemates, and as mixtures ofenantiomers and diastereomers. Typically, such compounds will beprepared as a racemic mixture. If desired, however, such compounds canbe prepared or isolated as pure stereoisomers, i.e., as individualenantiomers or diastereomers, or as stereoisomer-enriched mixtures. Asdiscussed in more detail below, individual stereoisomers of compoundsare prepared by synthesis from optically active starting materialscontaining the desired chiral centers or by preparation of mixtures ofenantiomeric products followed by separation or resolution, such asconversion to a mixture of diastereomers followed by separation orrecrystallization, chromatographic techniques, use of chiral resolvingagents, or direct separation of the enantiomers on chiralchromatographic columns. Starting compounds of particularstereochemistry are either commercially available or are made by themethods described below and resolved by techniques well-known in theart.

The term “enantiomers” means a pair of stereoisomers that arenon-superimposable mirror images of each other.

The terms “diastereoisomers” or “diastereomers” mean stereoisomers whichare not mirror images of each other.

The terms “racemic mixture” or “racemate” mean a mixture containingequal parts of individual enantiomers.

The term “non-racemic mixture” means a mixture containing unequal partsof individual enantiomers.

The term “geometrical isomer” means a stable isomer which results fromrestricted freedom of rotation about double bonds (e.g., cis-2-buteneand trans-2-butene) or in a cyclic structure (e.g.,cis-1,3-dichlorocyclobutane and trans-1,3-dichlorocyclobutane). Becausecarbon-carbon double (olefinic) bonds, C═N double bonds, cyclicstructures, and the like may be present in the compounds of theinvention, the invention contemplates each of the various stablegeometric isomers and mixtures thereof resulting from the arrangement ofsubstituents around these double bonds and in these cyclic structures.The substituents and the isomers are designated using the cis/transconvention or using the E or Z system, wherein the term “E” means higherorder substituents on opposite sides of the double bond, and the term“Z” means higher order substituents on the same side of the double bond.A thorough discussion of E and Z isomerism is provided in J. March,Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 4thed., John Wiley & Sons, 1992, which is hereby incorporated by referencein its entirety. Several of the following examples represent single Eisomers, single Z isomers, and mixtures of E/Z isomers. Determination ofthe E and Z isomers can be done by analytical methods such as x-raycrystallography, ¹H NMR, and ¹³C NMR.

Some of the compounds of the invention can exist in more than onetautomeric form. As mentioned above, the compounds of the inventioninclude all such tautomers.

It is well-known in the art that the biological and pharmacologicalactivity of a compound is sensitive to the stereochemistry of thecompound. Thus, for example, enantiomers often exhibit strikinglydifferent biological activity including differences in pharmacokineticproperties, including metabolism, protein binding, and the like, andpharmacological properties, including the type of activity displayed,the degree of activity, toxicity, and the like. Thus, one skilled in theart will appreciate that one enantiomer may be more active or mayexhibit beneficial effects when enriched relative to the otherenantiomer or when separated from the other enantiomer. Additionally,one skilled in the art would know how to separate, enrich, orselectively prepare the enantiomers of the compounds of the inventionfrom this disclosure and the knowledge of the prior art.

Thus, although the racemic form of drug may be used, it is often lesseffective than administering an equal amount of enantiomerically puredrug; indeed, in some cases, one enantiomer may be pharmacologicallyinactive and would merely serve as a simple diluent. For example,although ibuprofen had been previously administered as a racemate, ithas been shown that only the S-isomer of ibuprofen is effective as ananti-inflammatory agent (in the case of ibuprofen, however, although theR-isomer is inactive, it is converted in vivo to the S-isomer, thus, therapidity of action of the racemic form of the drug is less than that ofthe pure S-isomer). Furthermore, the pharmacological activities ofenantiomers may have distinct biological activity. For example,S-penicillamine is a therapeutic agent for chronic arthritis, whileR-penicillamine is toxic. Indeed, some purified enantiomers haveadvantages over the racemates, as it has been reported that purifiedindividual isomers have faster transdermal penetration rates compared tothe racemic mixture. See U.S. Pat. Nos. 5,114,946 and 4,818,541.

Thus, if one enantiomer is pharmacologically more active, less toxic, orhas a preferred disposition in the body than the other enantiomer, itwould be therapeutically more beneficial to administer that enantiomerpreferentially. In this way, the patient undergoing treatment would beexposed to a lower total dose of the drug and to a lower dose of anenantiomer that is possibly toxic or an inhibitor of the otherenantiomer.

Preparation of pure enantiomers or mixtures of desired enantiomericexcess (ee) or enantiomeric purity are accomplished by one or more ofthe many methods of (a) separation or resolution of enantiomers, or (b)enantioselective synthesis known to those of skill in the art, or acombination thereof. These resolution methods generally rely on chiralrecognition and include, for example, chromatography using chiralstationary phases, enantioselective host-guest complexation, resolutionor synthesis using chiral auxiliaries, enantioselective synthesis,enzymatic and nonenzymatic kinetic resolution, or spontaneousenantioselective crystallization. Such methods are disclosed generallyin Chiral Separation Techniques: A Practical Approach (2nd Ed.), G.Subramanian (ed.), Wiley-VCH, 2000; T. E. Beesley and R. P. W. Scott,Chiral Chromatograph, John Wiley & Sons, 1999; and Satinder Ahuja,Chiral Separations by Chromatograph, Am. Chem. Soc., 2000. Furthermore,there are equally well-known methods for the quantitation ofenantiomeric excess or purity, for example, GC, HPLC, CE, or NMR, andassignment of absolute configuration and conformation, for example, CDORD, X-ray crystallography, or NMR.

In general, all tautomeric forms and isomeric forms and mixtures,whether individual geometric isomers or stereoisomers or racemic ornon-racemic mixtures, of a chemical structure or compound is intended,unless the specific stereochemistry or isomeric form is specificallyindicated in the compound name or structure.

D. Pharmaceutical Administration and Diagnostic and Treatment Terms andConventions

The term “patient” includes both human and non-human mammals.

The term “effective amount” means an amount of a compound according tothe invention which, in the context of which it is administered or used,is sufficient to achieve the desired effect or result. Depending on thecontext, the term effective amount may include or be synonymous with apharmaceutically effective amount or a diagnostically effective amount.

The terms “pharmaceutically effective amount” or “therapeuticallyeffective amount” means an amount of a compound according to theinvention which, when administered to a patient in need thereof, issufficient to effect treatment for disease-states, conditions, ordisorders for which the compounds have utility. Such an amount would besufficient to elicit the biological or medical response of a tissue,system, or patient that is sought by a researcher or clinician.

The amount of a compound of according to the invention which constitutesa therapeutically effective amount will vary depending on such factorsas the compound and its biological activity, the composition used foradministration, the time of administration, the route of administration,the rate of excretion of the compound, the duration of treatment, thetype of disease-state or disorder being treated and its severity, drugsused in combination with or coincidentally with the compounds of theinvention, and the age, body weight, general health, sex, and diet ofthe patient. Such a therapeutically effective amount can be determinedroutinely by one of ordinary skill in the art having regard to their ownknowledge, the prior art, and this disclosure.

The term “diagnostically effective amount” means an amount of a compoundaccording to the invention which, when used in a diagnostic method,apparatus, or assay, is sufficient to achieve the desired diagnosticeffect or the desired biological activity necessary for the diagnosticmethod, apparatus, or assay. Such an amount would be sufficient toelicit the biological or medical response in a diagnostic method,apparatus, or assay, which may include a biological or medical responsein a patient or in a in vitro or in vivo tissue or system, that issought by a researcher or clinician. The amount of a compound accordingto the invention which constitutes a diagnostically effective amountwill vary depending on such factors as the compound and its biologicalactivity, the diagnostic method, apparatus, or assay used, thecomposition used for administration, the time of administration, theroute of administration, the rate of excretion of the compound, theduration of administration, drugs and other compounds used incombination with or coincidentally with the compounds of the invention,and, if a patient is the subject of the diagnostic administration, theage, body weight, general health, sex, and diet of the patient. Such adiagnostically effective amount can be determined routinely by one ofordinary skill in the art having regard to their own knowledge, theprior art, and this disclosure.

The term “modulate” means the ability of a compound to alter thefunction of the glucocorticoid receptor by, for example, binding to andstimulating or inhibiting the glucocorticoid receptor functionalresponses.

The term “modulator” in the context of describing compounds according tothe invention means a compound that modulates the glucocorticoidreceptor function. As such, modulators include, but are not limited to,agonists, partial agonists, antagonists, and partial antagonists.

The term “agonist” in the context of describing compounds according tothe invention means a compound that, when bound to the glucocorticoidreceptor, enhances or increases the glucocorticoid receptor function. Assuch, agonists include partial agonists and full agonists.

The term “full agonist” in the context of describing compounds accordingto the invention means a compound that evokes the maximal stimulatoryresponse from the glucocorticoid receptor, even when there are spare(unoccupied) glucocorticoid receptors present.

The term “partial agonist” in the context of describing compoundsaccording to the invention means a compound that is unable to evoke themaximal stimulatory response from the glucocorticoid receptor, even atconcentrations sufficient to saturate the glucocorticoid receptorspresent.

The term “antagonist” in the context of describing compounds accordingto the invention means a compound that directly or indirectly inhibitsor suppresses the glucocorticoid receptor function. As such, antagonistsinclude partial antagonists and full antagonists.

The term “full antagonist” in the context of describing compoundsaccording to the invention means a compound that evokes the maximalinhibitory response from the glucocorticoid receptor, even when thereare spare (unoccupied) glucocorticoid receptors present.

The term “partial antagonist” in the context of describing compoundsaccording to the invention means a compound that is unable to evoke themaximal inhibitory response from the glucocorticoid receptor, even atconcentrations sufficient to saturate the glucocorticoid receptorspresent.

The terms “treating” or “treatment” mean the treatment of adisease-state in a patient, and include:

-   -   (i) preventing the disease-state from occurring in a patient, in        particular, when such patient is genetically or otherwise        predisposed to the disease-state but has not yet been diagnosed        as having it;    -   (ii) inhibiting or ameliorating the disease-state in a patient,        i.e., arresting or slowing its development; or    -   (iii) relieving the disease-state in a patient, i.e., causing        regression or cure of the disease-state.        General Synthetic Methods for Making Compounds of Formula (I)

The invention also provides processes for making compounds of Formula(I). In all schemes, unless specified otherwise, R¹, R², R³, R⁴, R⁵, R⁶,and R⁷ in the formulas below shall have the meaning of R¹, R², R³, R⁴,R⁵, R⁶, and R⁷, in the Formula (I) of the invention describedhereinabove. Intermediates used in the preparation of compounds of theinvention are either commercially available or readily prepared bymethods known to those skilled in the art.

Optimum reaction conditions and reaction times may vary depending on theparticular reactants used. Unless otherwise specified, solvents,temperatures, pressures, and other reaction conditions may be readilyselected by one of ordinary skill in the art. Specific procedures areprovided in the Synthetic Examples section. Typically, reaction progressmay be monitored by thin layer chromatography (TLC), if desired, andintermediates and products may be purified by chromatography on silicagel and/or by recrystallization.

Compounds of Formula (I) where R⁷ is an optionally substituted indole orazaindole may be prepared by the method outlined in Scheme I.

As illustrated in Scheme I, the optionally substituted bromoketone (X)bearing R³ is reacted with hydroxylamine hydrochloride in a suitablesolvent, such as chloroform-water or methanol-water, to provide an oxime(XI). The oxime (XI) is reacted with a dienophile, for example, anindole (XII), in the presence of a base, such as sodium carbonate, in asuitable solvent, such as dichloromethane or tert-butylmethyl ether, toprovide oxime (XIII). The oxime (XIII) is treated with a suitablereducing agent, such as lithium aluminum hydride, in a suitable solvent,such as diethyl ether or THF, to provide an amine (XIV). The optionallysubstituted aminoethyl heterocycle (XIV) is reacted with a sulfonylchloride (VII) in pyridine or in dichloromethane in the presence of asuitable base, such as triethylamine, to provide the desired compound ofFormula (I).

The sulfonyl chlorides R²SO₂Cl (VII) and bromoketones (X) are eithercommercially available or may be readily prepared by methods known tothose skilled in the art. Intermediates (XIV) may also be commerciallyavailable or prepared by methods known in the art.

Compounds of Formula (I) may also be prepared using a more generalprocedure outlined in Scheme II. This general procedure is suitable fora variety of R³ and R⁵ where R⁷ is an optionally substituted heteroarylgroup.

As illustrated in Scheme II, the optionally substituted epoxide (IV)bearing R³ is reacted with sodium azide in the presence of ammoniumchloride in a suitable solvent, such as ethanol-water, to provide anazide (V). The azide (V) is reduced with a suitable catalyst, such as10% palladium on carbon, in a suitable solvent, such as methanol, underan atmosphere of hydrogen to provide an aminoalcohol (VI). Aminoalcohol(VI) is reacted with a sulfonyl chloride in a suitable solvent, such atTHF, in the presence of a suitable base, such sodium hydride, to providean aziridine (VIII). The aziridine (VIII) is reacted with a suitableorganometallic reagent R⁷-M where M is Li, Na, or MgX, and X is Br, Cl,or I (for this example R⁷ is indole) to provide the desired compound ofFormula (I).

Racemic and chiral epoxides (IV) and racemic and chiral aminoalcohols(VI) are either commercially available or may be readily prepared bymethods known to those skilled in the art. Aziridines (VIII) may also becommercially available or prepared from aminoalcohols by methods knownto those skilled in the art.

Another method of preparing compounds of Formula (I) where R³ is variedand R⁷ is an optionally substituted phenyl or a heteroaryl group isoutlined in Scheme III

As illustrated in Scheme III, the optionally substituted amino acidwhere R′ is H or an amino acid ester where R′ is Me or Et (XVI) bearingR³ is reacted with a sulfonyl chloride (VII) in a suitable solvent, suchas THF, in the presence of a suitable base, such as NaH, to providesulfonamide (XVI). Reduction of sulfonamide (XVI) with a suitablereducing agent, such as lithium aluminum hydride, provides alcohol(XVII). Ring closure by methods known in the art, for example, reactingthe alcohol with a sulfonyl chloride such a para-toluenesulfonylchloride in the presence of a suitable base, such as sodium hydride,provides the aziridine (VIII). The aziridine (VIII) is reacted with asuitable organometallic reagent (R⁷M), such as a Grignard reagent (M isMgX, and X is Br, Cl, or I) or an organolithium reagent (M is Li) in thepresence of a catalyst such as CuX (X is I, Br, or Cl) to provide thedesired compound of Formula (I). The racemic and chiral amino acids andamino acid esters (XVI) as well as the sulfonyl chlorides R²SO₂Cl (VII)are either commercially available or may be readily prepared by methodsknown to those skilled in the art. Hence, enantiomerically enrichedcompounds of Formula (1) may be prepared by using chiral startingmaterials. For example, a method of preparing 1,1,1-trifluoroalanine isgiven in V. A. Soloshonok et al., Tetrahedron, 1997, 53, 8307.

In order that this invention be more fully understood, the followingexamples are set forth. These examples are for the purpose ofillustrating embodiments of this invention, and are not to be construedas limiting the scope of the invention in any way since, as recognizedby one skilled in the art, particular reagents or conditions could bemodified as needed for individual compounds. Starting materials used areeither commercially available or easily prepared from commerciallyavailable materials by those skilled in the art.

EXPERIMENTAL EXAMPLES Example 1 Synthesis of2,4,6-Trimethyl-N-[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]benzenesulfonamide

To a solution of 10.5 mL (102.3 mmol) of1-bromo-3,3,3-trifluoropropan-2-one in 100 mL of chloroform (passedthrough a pad of basic Al₂O₃) was added a solution of 10.4 g (149.7mmol) of hydroxylamine hydrochloride in 20 mL of water and the mixturewas warmed at reflux. After 24 hours, the mixture was cooled and theorganic phase was separated. The aqueous layer was extracted with three30 mL portions of methylene chloride. The combined organic layers weredried over sodium sulfate, filtered, and concentrated in vacuo to afford11.5 g (55.7%) of 3-bromo-1,1,1-trifluoropropan-2-one oxime as a mixture(3:2) of geometric isomers.

To a solution of the 1.64 g (7.96 mmol) of3-bromo-1,1,1-trifluoropropan-2-one oxime in 250 mL of methyl tert-butylether was added 3.74 g (31.92 mmol) of indole followed by 5.0 g (47.62mmol) of powdered (freshly ground) sodium carbonate. The reaction wasmonitored by thin layer chromatography (ethyl acetate-hexanes (2:8)) toafford a new more polar product compared to indole (PMA-stained andUV-active). The mixture was then filtered through diatomaceous earth andconcentrated in vacuo. The residue was then concentrated in vacuo anddiluted first with dichloromethane (1 part) and then hexanes (4 parts)and passed through a pad of silica gel using dichloromethane-hexanes(gradient: 20%-100%) to afford 1.72 g (89.2%) of1,1,1-trifluoro-3-(1H-indol-3-yl)propan-2-one oxime as a white solid.

To a solution of 535 mg (2.21 mmol) of1,1,1-trifluoro-3-(1H-indol-3-yl)propan-2-one oxime in 25 mL of etherwas added 750 mg (19.76 mmol) of lithium aluminum hydride. The reactionwas monitored by proton NMR and thin layer chromatography (ethylacetate-hexanes (2:8)) which indicated a new more polar product than theoxime. After stirring overnight, the mixture was cautiously quenchedwith dropwise addition of water, dried over magnesium sulfate, filteredthrough diatomaceous earth, and concentrated in vacuo to afford 500 mg(99.2%) of crude amine which was used without further purification. A300 mg sample of this material was adsorbed onto silica gel and purifiedon silica gel using ethyl acetate-hexanes (gradient: 2%-20%) to afford200 mg (66%) of 2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethylamine as awhite solid.

A mixture of 42 mg (0.18 mmol) of2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethylamine and 45 mg, 0.21 mmol)of mesitylenesulfonyl chloride in 0.5 mL of pyridine was warmed to 45°C. The reaction was monitored by thin layer chromatography (ethylacetate-hexanes (3:7)) indicating a new less polar product compared tothe amine. After 6 hours, the mixture was cooled and diluted with 7 mLof 1 N aqueous HCl and extracted with three 7 mL portions of ethylacetate. The combined organic layers were washed with three 5 mLportions of 1 N aqueous HCl, 5 mL of brine, three 5 mL portions ofsaturated aqueous sodium bicarbonate, dried over magnesium sulfate,filtered, and concentrated in vacuo to afford 62 mg (82.1%) of crudesolid. The crude material was adsorbed onto silica gel andchromatographed on silica gel using dichloromethane-hexanes (gradient:50%-100%). The material from the column was crystallized fromether-hexanes to afford 52 mg (67%) of the title compounds as a whitesolid, m.p. 189° C.-191° C.; MS: m/z 409.15 (M-). Resolution to the (+)-and (−)-enantiomers was accomplished by chiral HPLC on a CHIRALCEL™ AD-Hcolumn, eluting with 12% isopropanol-hexanes.

Assessment of Biological Properties

Compounds of the invention were evaluated for binding to the steroidreceptor by a fluorescence polarization competitive binding assay.Detailed descriptions for preparation of recombinant glucocorticoidreceptor (GR) complex used in the assay is described in U.S. PatentApplication Publication No. US 2003/0017503, filed May 20, 2002, andincorporated herein by reference in its entirety. Preparation of thetetramethylrhodamine (TAMRA)-labeled dexamethasone probe wasaccomplished using a standard literature procedure (M. Pons et al., J.Steroid Biochem., 1985, 22, pp. 267-273).

A. Glucocorticoid Receptor Competitive Binding Assay

Step]. Characterization of the Fluorescent Probe

The wavelengths for maximum excitation and emission of the fluorescentprobe should first be measured. An example of such a probe is rhodamine(TAMRA)-labeled dexamethasone. The affinity of the probe for the steroidreceptor was then determined in a titration experiment. The fluorescencepolarization value of the probe in assay buffer was measured on anSLM-8100 fluorometer using the excitation and emission maximum valuesdescribed above. Aliquots of expression vector lysate were added andfluorescence polarization was measured after each addition until nofurther change in polarization value was observed. Non-linear leastsquares regression analysis was used to calculate the dissociationconstant of the probe from the polarization values obtained for lysatebinding to the probe.

Step 2. Screening for Inhibitors of Probe Binding

This assay uses fluorescence polarization (FP) to quantitate the abilityof test compounds to compete with tetramethylrhodamine (TAMRA)-labeleddexamethasone for binding to a human glucocorticoid receptor (GR)complex prepared from an insect expression system. The assay buffer was:10 mM TES, 50 mM KCl, 20 mM Na₂MoO₄.2H₂O, 1.5 mM EDTA, 0.04% w/v CHAPS,10% v/v glycerol, 1 mM dithiothreitol, pH 7.4. Test compounds weredissolved to 1 mM in neat DMSO and then further diluted to 10× assayconcentration in assay buffer supplemented with 10% v/v DMSO. Testcompounds were serially diluted at 10× assay concentrations in 10%DMSO-containing buffer in 96-well polypropylene plates. Binding reactionmixtures were prepared in 96-well black Dynex microtiter plates bysequential addition of the following assay components to each well: 15μL of 10× test compound solution, 85 μL of GR-containing baculoviruslysate diluted 1:170 in assay buffer, and 50 μL of 15 nM TAMRA-labeleddexamethasone. Positive controls were reaction mixtures containing notest compound; negative controls (blanks) were reaction mixturescontaining 0.7 μM to 2 μM dexamethasone. The binding reactions wereincubated for 1 hour at room temperature and then read for fluorescencepolarization in the LJL Analyst set to 550 nm excitation and 580 nmemission, with the Rhodamine 561 dichroic mirror installed. IC₅₀ valueswere determined by iterative non-linear curve fitting of the FP signaldata to a 4-parameter logistic equation.

Compounds found to bind to the glucocorticoid receptor may be evaluatedfor binding to the progesterone receptor (PR), estrogen receptor (ER),and mineralocorticoid receptors to evaluate the compound's selectivityfor GR. The protocols for PR and MR are identical to the above GRmethod, with the following exceptions: PR insect cell lysate is diluted1:7.1 and MR lysate diluted 1:9.4. PR probe is TAMRA-labeledmifepristone, used at a final concentration of 5 nM in the assay, andthe negative controls (blanks) were reactions containing mifepristone at0.7 μM to 2 μM.

The ER protocol is similar to the above protocols, but uses PanVera kitreceptor, fluorescein-labeled probe. The assay components are made inthe same volumes as above, to produce final assay concentrations for ERof 15 nM and ES2 probe of 1 nM. In addition, the component order ofaddition is modified from the above assays: probe is added to the platefirst, followed by receptor and test compound. The plates are read inthe LJL Analyst set to 485 nm excitation and 530 nm emission, with theFluorescein 505 dichroic mirror installed.

Compounds found to bind to the glucocorticoid receptor may be evaluatedfor dissociation of transactivation and transrepression by assays citedin the Background of the Invention (C. M. Bamberger and H. M. Schulte,Eur. J. Clin. Invest., 2000, 30 (suppl. 3) 6-9) or by the assaysdescribed below.

B. Glucocorticoid Receptor Cell Assays

1. Induction of Aromatase in Fibroblasts (Cell Assay forTransactivation)

Dexamethasone, a synthetic ligand to the glucocorticoid receptor (GR),induces expression of aromatase in human foreskin fibroblast cells. Theactivity of aromatase is measured by the conversion of testosterone toestradiol in culture media. Compounds that exhibit binding to GR areevaluated for their ability to induce aromatase activity in humanforeskin fibroblasts.

Human foreskin fibroblast cells (ATCC Cat. No. CRL-2429, designationCCD112SK) are plated on 96 well plates at 50,000 cells per well 5 daysbefore use, in Iscove's Modified Dulbecco's Media (GibcoBRL LifeTechnologies Cat No. 12440-053) supplemented with 10% charcoal filteredFBS (Clonetech Cat No. SH30068) and Gentamycin (GibcoBRL LifeTechnologies Cat. No. 15710-064). On the day of the experiment, themedia in the wells is replaced with fresh media. Cells are treated withtest compounds to final concentrations of 10⁻⁵ M to 10⁻⁸ M, andtestosterone to a final concentration of 300 ng/mL. Each well has atotal volume of 100 μL. Samples are made in duplicates. Control wellsinclude: (a) wells that receive testosterone only, and (b) wells thatreceive testosterone plus 2 μM of dexamethasone to provide maximuminduction of aromatase. Plates are incubated at 37° C. overnight (15 to18 hours), and supernatants are harvested at the end of incubation.Estradiol in the supernatant is measured using ELISA kits for estradiol(made by ALPCO, obtained from American Laboratory Products Cat. No.020-DR-2693) according to the manufacture's instruction. The amount ofestradiol is inversely proportional to the ELISA signals in each well.The extent of aromatase induction by test compounds is expressed as arelative percentage to dexamethasone. EC₅₀ values of test compounds arederived by non-linear curve fitting.

2. Inhibition of IL-6 Production in Fibroblasts (Cell Assay forTransrepression)

Human foreskin fibroblast cells produce IL-6 in response to stimulationby pro-inflammatory cytokine IL-1. This inflammatory response, asmeasured by the production of IL-6, can be effectively inhibited bydexamethasone, a synthetic ligand to the glucocorticoid receptor (GR).Compounds that exhibit binding to GR are evaluated for their ability toinhibit IL-6 production in human foreskin fibroblasts.

Human foreskin fibroblast cells (ATCC Cat. No. CRL-2429) are plated on96 well plates at 5,000 cells per well the day before use, in Iscove'sModified Dulbecco's Media (GibcoBRL Life Technologies Cat. No.12440-053) supplemented with 10% charcoal filtered FBS (Clonetech Cat.No. SH30068) and Gentamycin (GibcoBRL Life Technologies Cat. No.15710-064). On the next day, media in the wells is replaced with freshmedia. Cells are treated with IL-1 (rhIL-1α, R&D Systems Cat. No.200-LA) to a final concentration of 1 ng/mL, and with test compounds tofinal concentrations of 10⁻⁵ M to 10⁻⁸ M, in a total volume of 200 μLper well. Samples are done in duplicates. Background control wells donot receive test compounds or IL-1. Positive control wells receive IL-1only and represent maximum (or 100%) amount of IL-6 production. Platesare incubated at 37° C. overnight (15 to 18 hours), and supernatants areharvested at the end of incubation. IL-6 levels in the supernatants aredetermined by the ELISA kits for IL-6 (MedSystems Diagnostics GmbH,Vienna, Austria, Cat. No. BMS213TEN) according to manufacture'sinstructions. The extent of inhibition of IL-6 by test compounds isexpressed in percentage relative to positive controls. IC₅₀ values oftest compounds are derived by non-linear curve fitting.

Evaluation of agonist or antagonist activity of compounds binding to theglucocorticoid receptor may be determined by any of the assays.

3. Modulation of Tyrosine Aminotransferase (TAT) Induction in RatHepatoma Cells

Testing of compounds for agonist or antagonist activity in induction oftyrosine aminotransferase (TAT) in rat hepatoma cells.

H4-II-E-C3 cells were incubated overnight in 96 well plates (20,000cells/100 μL/well) in MEM medium containing 10% heat inactivated FBS and1% nonessential amino acids. On the next day, cells were stimulated withthe indicated concentrations of dexamethasone or test compound(dissolved in DMSO, final DMSO concentration 0.2%) for 18 hours. Controlcells were treated with 0.2% DMSO. After 18 hours, the cells were lysedin a buffer containing 0.1% Triton X-100 and the TAT activity wasmeasured in a photometric assay using tyrosine and alpha-ketoglutarateas substrates.

For measuring antagonist activity, the hepatoma cells werepre-stimulated by addition of dexamethasone (concentration ranges from3×10⁻⁹ M to 3×10⁻⁸ M) shortly before the test compound was applied tothe cells. The steroidal non-selective GR/PR antagonist mifepristone wasused as control.

4. Modulation of MMTV-Luc Induction in HeLa Cells

Testing of compounds for agonist or antagonist activity in stimulationof MMTV-(mouse mammary tumor virus) promoter in HeLa cells.

HeLa cells were stably co-transfected with the pHHLuc-plasmid containinga fragment of the MMTV-LTR (−200 to +100 relative to the transcriptionstart site) cloned in front of the luciferase gene (Norden, 1988) andthe pcDNA3.1 plasmid (Invitrogen) constitutively expressing theresistance for the selective antibiotic GENETICIN®. Clones with bestinduction of the MMTV-promoter were selected and used for furtherexperiments.

Cells were cultured overnight in DMEM medium without phenol red,supplemented with 3% CCS (charcoal treated calf serum) and thentransferred to 96 well plates (15,000 cells/100 μL/well). On the nextday, activation of the MMTV-promoter was stimulated by addition of testcompound or dexamethasone dissolved in DMSO (final concentration 0.2%).Control cells were treated with DMSO only. After 18 hours, the cellswere lysed with cell lysis reagent (Promega, Cat. No. E1531), luciferaseassay reagent (Promega, Cat. No. E1501) was added and the glowluminescence was measured using a luminometer (BMG, Offenburg).

For measuring antagonist activity, the MMTV-promoter was pre-stimulatedby adding dexamethasone (3×10⁻⁹ M to 3×10⁻⁸ M) shortly before the testcompound was applied to the cells. The steroidal non-selective GR/PRantagonist mifepristone was used as control.

5. Modulation of IL-8 Production in U937 Cells

Testing of compounds for agonist or antagonist activity in GR-mediatedinhibition of LPS-induced IL-8 secretion in U-937 cells.

U-937 cells were incubated for 2 to 4 days in RPMI1640 medium containing10% CCS (charcoal treated calf serum). The cells were transferred to 96well plates (40,000 cells/100 μL/well) and stimulated with 1 μg/mL LPS(dissolved in PBS) in the presence or absence of dexamethasone or testcompound (dissolved in DMSO, final concentration 0.2%). Control cellswere treated with 0.2% DMSO. After 18 hours, the IL-8 concentration inthe cell supernatant was measured by ELISA, using the “OptEIA human IL-8set” (Pharmingen, Cat. No. 2654KI).

For measuring antagonist activity, the LPS-induced IL-8 secretion wasinhibited by adding dexamethasone (3×10⁻⁹ M to 3×10⁻⁸ M) shortly beforethe test compound was applied to the cells. The steroidal non-selectiveGR/PR antagonist mifepristone was used as control.

6. Modulation of ICAM-Luc Expression in HeLa Cells

Testing of compounds for agonist or antagonist activity in inhibition ofTNF-alpha-induced activation of the ICAM-promoter in HeLa cells. HeLacells were stably co-transfected with a plasmid containing a 1.3 kbfragment of the human ICAM-promoter (−1353 to −9 relative to thetranscription start site, Ledebur and Parks, 1995) cloned in front ofthe luciferase gene and the pcDNA3.1 plasmid (Invitrogen) whichconstitutively expresses the resistance for the antibiotic GENETICIN®.Clones with best induction of the ICAM-promoter were selected and usedfor further experiments. Cells were transferred to 96 well plates(15,000 cells/100 μL/well) in DMEM medium supplemented with 3% CCS. Onthe following day the activation of the ICAM-promoter was induced byaddition of 10 ng/mL recombinant TNF-alpha (R&D System, Cat. No.210-TA). Simultaneously the cells were treated with the test compound ordexamethasone (dissolved in DMSO, final concentration 0.2%). Controlcells were treated with DMSO only. After 18 hours, the cells were lysedwith cell lysis reagent (Promega, Cat. No. E1531), luciferase assayreagent (Promega, Cat. No. E1501) was added and glow luminescence wasmeasured using a luminometer (BMG, Offenburg).

For measuring antagonist activity, the TNF-alpha-induced activation ofthe ICAM-promoter was inhibited by adding dexamethasone (3×10⁻⁹ M to3×10⁻⁸ M) shortly before the test compound was applied to the cells. Thesteroidal non-selective GR/PR antagonist mifepristone was used ascontrol.

In general, the preferred potency range in the above assays is between0.1 nM and 10 μM, the more preferred potency range is 0.1 nM to 1 μM,and the most preferred potency range is 0.1 nM to 100 nM.

Representative compounds of the invention have been tested and haveshown activity as modulators of the glucocorticoid receptor function inone or more of the above assays. For example, the following compounds ofthe invention have demonstrated potent activity (100 nM or less) in theGR binding assay:

-   2,4,6-Trimethyl-N-[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;-   2,4,6-Triisopropyl-N-[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;-   2,4,6-Trimethyl-N-[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;-   2-Amino-4,6-dichloro-N-[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;-   2,4,6-Trimethyl-N-[2,2,2-trifluoro-1-(7-methyl-1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;-   N-[1-(5-Bromo-1H-indol-3-ylmethyl)-2,2,2-trifluoroethyl]-2,4,6-trimethylbenzenesulfonamide;-   N-[1-(4-Bromo-1H-indol-3-ylmethyl)-2,2,2-trifluoroethyl]-2,4,6-trimethylbenzenesufonamide;-   2,4,6-Trimethyl-N-[2,2,2-trifluoro-1-(4-methyl-1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;-   2,4,6-Trimethyl-N-[2,2,2-trifluoro-1-(6-methyl-1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;-   4-Bromo-2,6-dichloro-N-[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;-   2,4,6-Trimethyl-N-[2,2,2-trifluoro-1-(5-methyl-1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;-   2-Amino-4,6-dichloro-N-[2,2,2-trifluoro-1-(5-methyl-1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;    and-   2,4-Dichloro-6-methoxy-N-[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]benzenesulfonamide.

In addition, the following compounds of the invention have been testedand have shown activity as an agonist of the glucocorticoid receptorfunction in one or more of the above assays:

-   2,4,6-Trimethyl-N-[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;-   2-Amino-4,6-dichloro-N-[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;-   2-Amino-4,6-dichloro-N-[2,2,2-trifluoro-1-(5-methyl-1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;    and-   2,4,6-Trimethyl-N-[2,2,2-trifluoro-1-(5-methyl-1H-indol-3-ylmethyl)ethyl]benzenesulfonamide.    7. Inhibition of Osteocalcin Production from Osteoblast Cell Line    MG-63

Human osteosarcoma MG-63 cells (ATCC, Cat. No. CRL-1427) are plated on96 well plates at 20,000 cells per well the day before use in 200 μLmedia of 99% D-MEM/F-12 (Gibco-Invitrogen, Cat. No. 11039-021),supplemented with 1% penicillin and streptomycin (Gibco-Invitrogen, Cat.No. 15140-122), 10 μg/mL Vitamin C (Sigma, Cat. No. A-4544), and 1%charcoal filtered Fetal Bovine Serum (HyClone, Cat. No. SH30068.02). Thenext day, wells are replaced with fresh media. Cells are treated withVitamin D (Sigma, Cat. No. D1530) to a final concentration of 10 nM, andwith the test compounds in concentrations of 10⁻⁶ M to 10⁻⁹ M, in atotal volume of 200 μL per well. Samples are done in duplicates.Background control wells do not receive Vitamin D or compounds. Positivecontrol wells receive Vitamin D only, without compounds, and representmaximum (100%) amount of osteocalcin production. Plates are incubated at37° C. incubator for 48 hours and supernatants are harvested at the endof incubation. Amounts of osteocalcin in the supernatants are determinedby the Glype osteocalcin ELISA kit (Zymed, Cat. No. 99-0054) accordingto manufacture's protocol. Inhibition of osteocalcin by test compoundsis expressed in percentage relative to positive controls. IC₅₀ values ofthe test compounds are derived by non-lineal curve fitting.

The invention also provides methods of modulating the glucocorticoidreceptor function in a patient comprising administering to the patient acompound according to the invention. If the purpose of modulating theglucocorticoid receptor function in a patient is to treat adisease-state or condition, the administration preferably comprises atherapeutically or pharmaceutically effective amount of apharmaceutically acceptable compound according to the invention. If thepurpose of modulating the glucocorticoid receptor function in a patientis for a diagnostic or other purpose (e.g., to determine the patient'ssuitability for therapy or sensitivity to various sub-therapeutic dosesof the compounds according to the invention), the administrationpreferably comprises an effective amount of a compound according to theinvention, that is, the amount necessary to obtain the desired effect ordegree of modulation.

Methods of Therapeutic Use

As pointed out above, the compounds of the invention are useful inmodulating the glucocorticoid receptor function. In doing so, thesecompounds have therapeutic use in treating disease-states and conditionsmediated by the glucocorticoid receptor function or that would benefitfrom modulation of the glucocorticoid receptor function.

As the compounds of the invention modulate the glucocorticoid receptorfunction, they have very useful anti-inflammatory and antiallergic,immune-suppressive, and anti-proliferative activity and they can be usedin patients as drugs, particularly in the form of pharmaceuticalcompositions as set forth below, for the treatment of disease-states andconditions.

The agonist compounds according to the invention can be used in patientsas drugs for the treatment of the following disease-states orindications that are accompanied by inflammatory, allergic, and/orproliferative processes:

-   (i) Lung diseases: chronic, obstructive lung diseases of any    genesis, particularly bronchial asthma and chronic obstructive    pulmonary disease (COPD); adult respiratory distress syndrome    (ARDS); bronchiectasis; bronchitis of various genesis; all forms of    restrictive lung diseases, particularly allergic alveolitis; all    forms of lung edema, particularly toxic lung edema; all forms of    interstitial lung diseases of any genesis, e.g., radiation    pneumonitis; and sarcoidosis and granulomatoses, particularly Boeck    disease;-   (ii) Rheumatic diseases or autoimmune diseases or joint diseases:    all forms of rheumatic diseases, especially rheumatoid arthritis,    acute rheumatic fever, and polymyalgia rheumatica; reactive    arthritis; rheumatic soft tissue diseases; inflammatory soft tissue    diseases of other genesis; arthritic symptoms in degenerative joint    diseases (arthroses); traumatic arthritis; collagenoses of any    genesis, e.g., systemic lupus erythematosus, scleroderma,    polymyositis, dermatomyositis, Sjögren syndrome, Still disease, and    Felty syndrome;-   (iii) Allergic diseases: all forms of allergic reactions, e.g.,    angioneurotic edema, hay fever, insect bites, allergic reactions to    drugs, blood derivatives, contrast agents, etc., anaphylactic shock    (anaphylaxis), urticaria, angioneurotic edema, and contact    dermatitis;-   (iv) Vasculitis diseases: panarteritis nodosa, polyarteritis nodosa,    arteritis temporalis, Wegner granulomatosis, giant cell arthritis,    and erythema nodosum;-   (v) Dermatological diseases: atopic dermatitis, particularly in    children; psoriasis; pityriasis rubra pilaris; erythematous diseases    triggered by various noxa, e.g., rays, chemicals, burns, etc.;    bullous dermatoses; diseases of the lichenoid complex; pruritus    (e.g., of allergic genesis); seborrheic dermatitis; rosacea;    pemphigus vulgaris; erythema multiforme exudativum; balanitis;    vulvitis; hair loss, such as occurs in alopecia greata; and    cutaneous T cell lymphomas;-   (vi) Renal diseases: nephrotic syndrome; and all types of nephritis,    e.g., glomerulonephritis;-   (vii) Hepatic diseases: acute liver cell disintegration; acute    hepatitis of various genesis, e.g., viral, toxic, drug-induced; and    chronically aggressive and/or chronically intermittent hepatitis;-   (viii) Gastrointestinal diseases: inflammatory bowel diseases, e.g.,    regional enteritis (Crohn disease), colitis ulcerosa; gastritis;    peptic esophagitis (refluxoesophagitis); and gastroenteritis of    other genesis, e.g., nontropical sprue;-   (ix) Proctological diseases: anal eczema; fissures; hemorrhoids; and    idiopathic proctitis;-   (x) Eye diseases: allergic keratitis, uveitis, or iritis;    conjunctivitis; blepharitis; neuritis nervi optici; choroiditis; and    sympathetic ophthalmia;-   (xi) Diseases of the ear, nose, and throat (ENT) area: allergic    rhinitis or hay fever; otitis extema, e.g., caused by contact    eczema, infection, etc.; and otitis media;-   (xii) Neurological diseases: brain edema, particularly tumor-related    brain edema; multiple sclerosis; acute encephalomyelitis;    meningitis; acute spinal cord injury; stroke; and various forms of    seizures, e.g., nodding spasms;-   (xiii) Blood diseases: acquired hemolytic anemia; and idiopathic    thrombocytopenia;-   (xiv) Tumor diseases: acute lymphatic leukemia; malignant lymphoma;    lymphogranulomatoses; lymphosarcoma; extensive metastases,    particularly in mammary, bronchial, and prostatic carcinoma;-   (xv) Endocrine diseases: endocrine ophthalmopathy; endocrine    orbitopathia; thyrotoxic crisis; Thyroiditis de Quervain; Hashimoto    thyroiditis; Morbus Basedow; granulomatous thyroiditis; struma    lymphomatosa; and Grave disease;-   (xvi) Organ and tissue transplantations and graft-versus-host    diseases;-   (xvii) Severe states of shock, e.g., septic shock, anaphylactic    shock, and systemic inflammatory response syndrome (SIRS);-   (xviii) Substitution therapy in: congenital primary adrenal    insufficiency, e.g., adrenogenital syndrome; acquired primary    adrenal insufficiency, e.g., Addison disease, autoimmune    adrenalitis, post-infection, tumors, metastases, etc.; congenital    secondary adrenal insufficiency, e.g., congenital hypopituitarism;    and acquired secondary adrenal insufficiency, e.g., post-infection,    tumors, metastases, etc.;-   (xix) Pain of inflammatory genesis, e.g., lumbago; and-   (xx) various other disease-states or conditions including type I    diabetes (insulin-dependent diabetes), osteoarthritis,    Guillain-Barre syndrome, restenosis following percutaneous    transluminal coronary angioplasty, Alzheimer disease, acute and    chronic pain, atherosclerosis, reperfusion injury, bone resorption    diseases, congestive heart failure, myocardial infarction, thermal    injury, multiple organ injury secondary to trauma, acute purulent    meningitis, necrotizing enterocolitis and syndromes associated with    hemodialysis, leukopheresis, and granulocyte transfusion.

In addition, the compounds according to the invention can be used forthe treatment of any other disease-states or conditions not mentionedabove which have been treated, are treated, or will be treated withsynthetic glucocorticoids (see, e.g., H. J. Hatz, Glucocorticoide:Immunologische Grundlagen, Pharmakologie und Therapierichtlinien[Glucocorticoids: Immunological Fundamentals, Pharmacology, andTherapeutic Guidelines], Stuttgart: Verlagsgesellschaft mbH, 1998, whichis hereby incorporated by reference in its entirety). Most or all of theindications (i) through (xx) mentioned above are described in detail inH. J. Hatz, Glucocorticoide: Immunologische Grundlagen, Pharmakologieund Therapierichtlinien. Furthermore, the compounds of the invention canalso be used to treat disorders other than those listed above ormentioned or discussed herein, including in the Background of theInvention.

The antagonist compounds according to the invention, whether fullantagonists or partial antagonists, can be used in patients as drugs forthe treatment of the following disease-states or indications, withoutlimitation: type II diabetes (non-insulin-dependent diabetes); obesity;cardiovascular diseases; hypertension; arteriosclerosis; neurologicaldiseases, such as psychosis and depression; adrenal and pituitarytumors; glaucoma; and Cushing syndrome based on an ACTH-secreting tumorlike pituitary adenoma. In particular, the compounds of the inventionare useful for treating obesity and all disease-states and indicationsrelated to a deregulated fatty acids metabolism such as hypertension,atherosclerosis, and other cardiovascular diseases. Using the compoundsof the invention that are GR antagonists, it should be possible toantagonize both the carbohydrate metabolism and fatty acids metabolism.Thus, the antagonist compounds of the invention are useful in treatingall disease-states and conditions that involve increased carbohydrate,protein, and lipid metabolism and would include disease-states andconditions leading to catabolism like muscle frailty (as an example ofprotein metabolism).

Methods of Diagnostic Use

The compounds of the invention may also be used in diagnosticapplications and for commercial and other purposes as standards incompetitive binding assays. In such uses, the compounds of the inventionmay be used in the form of the compounds themselves or they may bemodified by attaching a radioisotope, luminescence, fluorescent label orthe like in order to obtain a radioisotope, luminescence, or fluorescentprobe, as would be known by one of skill in the art and as outlined inHandbook of Fluorescent Probes and Research Chemicals, 6th Edition, R.P. Haugland (ed.), Eugene: Molecular Probes, 1996; Fluorescence andLuminescence Probes for Biological Activity, W. T. Mason (ed.), SanDiego: Academic Press, 1993; Receptor-Ligand Interaction, A PracticalApproach, E. C. Hulme (ed.), Oxford: IRL Press, 1992, each of which ishereby incorporated by reference in their entireties.

General Administration and Pharmaceutical Compositions

When used as pharmaceuticals, the compounds of the invention aretypically administered in the form of a pharmaceutical composition. Suchcompositions can be prepared using procedures well known in thepharmaceutical art and comprise at least one compound of the invention.The compounds of the invention may also be administered alone or incombination with adjuvants that enhance stability of the compounds ofthe invention, facilitate administration of pharmaceutical compositionscontaining them in certain embodiments, provide increased dissolution ordispersion, increased inhibitory activity, provide adjunct therapy, andthe like. The compounds according to the invention may be used on theirown or in conjunction with other active substances according to theinvention, optionally also in conjunction with other pharmacologicallyactive substances. In general, the compounds of this invention areadministered in a therapeutically or pharmaceutically effective amount,but may be administered in lower amounts for diagnostic or otherpurposes.

In particular, the compounds of the invention are useful in combinationwith glucocorticoids or corticosteroids. As pointed out above, standardtherapy for a variety of immune and inflammatory disorders includesadministration of corticosteroids, which have the ability to suppressimmunologic and inflammatory responses. (A. P. Truhan et al., Annals ofAllergy, 1989, 62, pp. 375-391; J. D. Baxter, Hospital Practice, 1992,27, pp. 111-134; R. P. Kimberly, Curr. Opin. Rheumatol., 1992, 4, pp.325-331; M. H. Weisman, Curr. Opin. Rheumatol., 1995, 7, pp. 183-190; W.Sterry, Arch. Dermatol. Res., 1992, 284 (Suppl.), pp. S27-S29). Whiletherapeutically beneficial, however, the use of corticosteroids isassociated with a number of side effects, ranging from mild to possiblylife threatening, especially with prolonged and/or high dose steroidusage. Accordingly, methods and compositions that enable the use of alower effective dosage of corticosteroids (referred to as the “steroidsparing effect”) would be highly desirable to avoid unwanted sideeffects. The compounds of the invention provide such a steroid sparingeffect by achieving the desired therapeutic effect while allowing theuse of lower doses and less frequent administration of glucocorticoidsor corticosteroids.

Administration of the compounds of the invention, in pure form or in anappropriate pharmaceutical composition, can be carried out using any ofthe accepted modes of administration of pharmaceutical compositions.Thus, administration can be, for example, orally, buccally (e.g.,sublingually), nasally, parenterally, topically, transdermally,vaginally, or rectally, in the form of solid, semi-solid, lyophilizedpowder, or liquid dosage forms, such as, for example, tablets,suppositories, pills, soft elastic and hard gelatin capsules, powders,solutions, suspensions, or aerosols, or the like, preferably in unitdosage forms suitable for simple administration of precise dosages. Thepharmaceutical compositions will generally include a conventionalpharmaceutical carrier or excipient and a compound of the invention asthe/an active agent, and, in addition, may include other medicinalagents, pharmaceutical agents, carriers, adjuvants, diluents, vehicles,or combinations thereof. Such pharmaceutically acceptable excipients,carriers, or additives as well as methods of making pharmaceuticalcompositions for various modes or administration are well-known to thoseof skill in the art. The state of the art is evidenced, e.g., byRemington: The Science and Practice of Pharmacy, 20th Edition, A.Gennaro (ed.), Lippincott Williams & Wilkins, 2000; Handbook ofPharmaceutical Additives, Michael & Irene Ash (eds.), Gower, 1995;Handbook of Pharmaceutical Excipients, A. H. Kibbe (ed.), AmericanPharmaceutical Ass'n, 2000; H. C. Ansel and N. G. Popovish,Pharmaceutical Dosage Forms and Drug Delivery Systems, 5th ed., Lea andFebiger, 1990; each of which is incorporated herein by reference intheir entireties to better describe the state of the art.

As one of skill in the art would expect, the forms of the compounds ofthe invention utilized in a particular pharmaceutical formulation willbe selected (e.g., salts) that possess suitable physical characteristics(e.g., water solubility) that is required for the formulation to beefficacious.

Pharmaceutical compositions suitable for buccal (sub-lingual)administration include lozenges comprising a compound of the presentinvention in a flavored base, usually sucrose, and acacia or tragacanth,and pastilles comprising the compound in an inert base such as gelatinand glycerin or sucrose and acacia.

Pharmaceutical compositions suitable for parenteral administrationcomprise sterile aqueous preparations of a compound of the presentinvention. These preparations are preferably administered intravenously,although administration can also be effected by means of subcutaneous,intramuscular, or intradermal injection. Injectable pharmaceuticalformulations are commonly based upon injectable sterile saline,phosphate-buffered saline, oleaginous suspensions, or other injectablecarriers known in the art and are generally rendered sterile andisotonic with the blood. The injectable pharmaceutical formulations maytherefore be provided as a sterile injectable solution or suspension ina nontoxic parenterally acceptable diluent or solvent, including1,3-butanediol, water, Ringer's solution, isotonic sodium chloridesolution, fixed oils such as synthetic mono- or diglycerides, fattyacids such as oleic acid, and the like. Such injectable pharmaceuticalformulations are formulated according to the known art using suitabledispersing or setting agents and suspending agents. Injectablecompositions will generally contain from 0.1 to 5% w/w of a compound ofthe invention.

Solid dosage forms for oral administration of the compounds includecapsules, tablets, pills, powders, and granules. For such oraladministration, a pharmaceutically acceptable composition containing acompound(s) of the invention is formed by the incorporation of any ofthe normally employed excipients, such as, for example, pharmaceuticalgrades of mannitol, lactose, starch, pregelatinized starch, magnesiumstearate, sodium saccharine, talcum, cellulose ether derivatives,glucose, gelatin, sucrose, citrate, propyl gallate, and the like. Suchsolid pharmaceutical formulations may include formulations, as are wellknown in the art, to provide prolonged or sustained delivery of the drugto the gastrointestinal tract by any number of mechanisms, whichinclude, but are not limited to, pH sensitive release from the dosageform based on the changing pH of the small intestine, slow erosion of atablet or capsule, retention in the stomach based on the physicalproperties of the formulation, bioadhesion of the dosage form to themucosal lining of the intestinal tract, or enzymatic release of theactive drug from the dosage form.

Liquid dosage forms for oral administration of the compounds includeemulsions, microemulsions, solutions, suspensions, syrups, and elixirs,optionally containing pharmaceutical adjuvants in a carrier, such as,for example, water, saline, aqueous dextrose, glycerol, ethanol and thelike. These compositions can also contain additional adjuvants such aswetting, emulsifying, suspending, sweetening, flavoring, and perfumingagents.

Topical dosage forms of the compounds include ointments, pastes, creams,lotions, gels, powders, solutions, sprays, inhalants, eye ointments, eyeor ear drops, impregnated dressings and aerosols, and may containappropriate conventional additives such as preservatives, solvents toassist drug penetration and emollients in ointments and creams. Topicalapplication may be once or more than once per day depending upon theusual medical considerations. Furthermore, preferred compounds for thepresent invention can be administered in intranasal form via topical useof suitable intranasal vehicles. The formulations may also containcompatible conventional carriers, such as cream or ointment bases andethanol or oleyl alcohol for lotions. Such carriers may be present asfrom about 1% up to about 98% of the formulation, more usually they willform up to about 80% of the formulation.

Transdermal administration is also possible. Pharmaceutical compositionssuitable for transdermal administration can be presented as discretepatches adapted to remain in intimate contact with the epidermis of therecipient for a prolonged period of time. To be administered in the formof a transdermal delivery system, the dosage administration will, ofcourse, be continuous rather than intermittent throughout the dosageregimen. Such patches suitably contain a compound of the invention in anoptionally buffered, aqueous solution, dissolved and/or dispersed in anadhesive, or dispersed in a polymer. A suitable concentration of theactive compound is about 1% to 35%, preferably about 3% to 15%.

For administration by inhalation, the compounds of the invention areconveniently delivered in the form of an aerosol spray from a pump spraydevice not requiring a propellant gas or from a pressurized pack or anebulizer with the use of a suitable propellant, e.g.,dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, tetrafluoroethane, heptafluoropropane, carbondioxide, or other suitable gas. In any case, the aerosol spray dosageunit may be determined by providing a valve to deliver a metered amountso that the resulting metered dose inhaler (MDI) is used to administerthe compounds of the invention in a reproducible and controlled way.Such inhaler, nebulizer, or atomizer devices are known in the art, forexample, in PCT International Publication Nos. WO 97/12687 (particularlyFIG. 6 thereof, which is the basis for the commercial RESPIMAT®nebulizer); WO 94/07607; WO 97/12683; and WO 97/20590, to whichreference is hereby made and each of which is incorporated herein byreference in their entireties.

Rectal administration can be effected utilizing unit dose suppositoriesin which the compound is admixed with low-melting water-soluble orinsoluble solids such as fats, cocoa butter, glycerinated gelatin,hydrogenated vegetable oils, mixtures of polyethylene glycols of variousmolecular weights, or fatty acid esters of polyethylene glycols, or thelike. The active compound is usually a minor component, often from about0.05 to 10% by weight, with the remainder being the base component.

In all of the above pharmaceutical compositions, the compounds of theinvention are formulated with an acceptable carrier or excipient. Thecarriers or excipients used must, of course, be acceptable in the senseof being compatible with the other ingredients of the composition andmust not be deleterious to the patient. The carrier or excipient can bea solid or a liquid, or both, and is preferably formulated with thecompound of the invention as a unit-dose composition, for example, atablet, which can contain from 0.05% to 95% by weight of the activecompound. Such carriers or excipients include inert fillers or diluents,binders, lubricants, disintegrating agents, solution retardants,resorption accelerators, absorption agents, and coloring agents.Suitable binders include starch, gelatin, natural sugars such as glucoseor β-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth or sodium alginate, carboxymethylcellulose,polyethylene glycol, waxes, and the like. Lubricants include sodiumoleate, sodium stearate, magnesium stearate, sodium benzoate, sodiumacetate, sodium chloride, and the like. Disintegrators include starch,methyl cellulose, agar, bentonite, xanthan gum, and the like.

Generally, a therapeutically effective daily dose is from about 0.001 mgto about 15 mg/kg of body weight per day of a compound of the invention;preferably, from about 0.1 mg to about 10 mg/kg of body weight per day;and most preferably, from about 0.1 mg to about 1.5 mg/kg of body weightper day. For example, for administration to a 70 kg person, the dosagerange would be from about 0.07 mg to about 1050 mg per day of a compoundof the invention, preferably from about 7.0 mg to about 700 mg per day,and most preferably from about 7.0 mg to about 105 mg per day. Somedegree of routine dose optimization may be required to determine anoptimal dosing level and pattern.

Pharmaceutically acceptable carriers and excipients encompass all theforegoing additives and the like.

Examples of Pharmaceutical Formulations

A. TABLETS Component Amount per tablet (mg) active substance 100 lactose140 corn starch 240 polyvinylpyrrolidone 15 magnesium stearate 5 TOTAL500

The finely ground active substance, lactose, and some of the corn starchare mixed together. The mixture is screened, then moistened with asolution of polyvinylpyrrolidone in water, kneaded, wet-granulated anddried. The granules, the remaining corn starch and the magnesiumstearate are screened and mixed together. The mixture is compressed toproduce tablets of suitable shape and size. B. TABLETS Component Amountper tablet (mg) active substance 80 lactose 55 corn starch 190polyvinylpyrrolidone 15 magnesium stearate 2 microcrystalline cellulose35 sodium-carboxymethyl starch 23 TOTAL 400

The finely ground active substance, some of the corn starch, lactose,microcrystalline cellulose, and polyvinylpyrrolidone are mixed together,the mixture is screened and worked with the remaining corn starch andwater to form a granulate which is dried and screened. Thesodium-carboxymethyl starch and the magnesium stearate are added andmixed in and the mixture is compressed to form tablets of a suitablesize. C. COATED TABLETS Component Amount per tablet (mg) activesubstance 5 lactose 30 corn starch 41.5 polyvinylpyrrolidone 3 magnesiumstearate 0.5 TOTAL 90

The active substance, corn starch, lactose, and polyvinylpyrrolidone arethoroughly mixed and moistened with water. The moist mass is pushedthrough a screen with a 1 mm mesh size, dried at about 45° C. and thegranules are then passed through the same screen. After the magnesiumstearate has been mixed in, convex tablet cores with a diameter of 6 mmare compressed in a tablet-making machine. The tablet cores thusproduced are coated in known manner with a covering consistingessentially of sugar and talc. The finished coated tablets are polishedwith wax. D. CAPSULES Component Amount per capsule (mg) active substance50 corn starch 268.5 magnesium stearate 1.5 TOTAL 320

The substance and corn starch are mixed and moistened with water. Themoist mass is screened and dried. The dry granules are screened andmixed with magnesium stearate. The finished mixture is packed into size1 hard gelatine capsules. E. AMPOULE SOLUTION Component Amount perampoule active substance 50 mg sodium chloride 50 mg water for inj.   5mL

The active substance is dissolved in water at its own pH or optionallyat pH 5.5 to 6.5 and sodium chloride is added to make it isotonic. Thesolution obtained is filtered free from pyrogens and the filtrate istransferred under aseptic conditions into ampoules which are thensterilized and sealed by fusion. The ampoules contain 5 mg, 25 mg, and50 mg of active substance. F. SUPPOSITORIES Component Amount persuppository (mg) active substance 50 solid fat 1650 TOTAL 1700

The hard fat is melted. At 40° C., the ground active substance ishomogeneously dispersed therein. The mixture is cooled to 38° C. andpoured into slightly chilled suppository molds. G. METERING AEROSOLComponent Amount active substance 0.005 sorbitan trioleate 0.1monofluorotrichloromethane and to 100 difluorodichloromethane (2:3)

The suspension is transferred into a conventional aerosol container witha metering valve. Preferably, 50 μL of suspension are delivered perspray. The active substance may also be metered in higher doses ifdesired (e.g., 0.02% by weight). Component Amount H. POWDER FORINHALATION active substance 1.0 mg lactose monohydrate to 25 mg I.POWDER FOR INHALATION active substance 2.0 mg lactose monohydrate to 25mg J. POWDER FOR INHALATION active substance 1.0 mg lactose monohydrateto 5 mg K. POWDER FOR INHALATION active substance 2.0 mg lactosemonohydrate to 5 mg

In Examples H, I, J, and K, the powder for inhalation is produced in theusual way by mixing the individual ingredients together.

1. A compound of Formula (I)

wherein: R¹ is hydrogen or C₁-C₃ alkyl, each optionally independentlysubstituted with one to three substituent groups selected from hydroxy,halogen, or oxo; R² is aryl optionally independently substituted withone to five substituent groups, wherein each substituent group of R² isindependently C₁-C₅ alkyl, C₂-C₃ alkenyl, C₂-C₃ alkynyl, C₁-C₅ alkoxy,hydroxy, nitro, trifluoromethyl, trifluoromethoxy, halogen, cyano,acylamino, C₁-C₅ alkoxycarbonylamino, C₁-C₅ alkylsulfonylamino, C₁-C₅alkylthio, amino wherein the nitrogen atom is optionally independentlymono- or di-substituted by C₁-C₅ alkyl, or ureido wherein eithernitrogen atom is optionally independently substituted with C₁-C₅ alkyl,wherein each substituent group of R² is optionally independentlysubstituted with C₁-C₃ alkyl, halogen, hydroxyl, or amino; R³ is C₁-C₈alkyl independently substituted with one to five substituent groups,wherein each substituent group of R³ is independently C₃-C₆ cycloalkyl,aryl, halogen, trifluoromethyl, trifluoromethoxy, or trifluoromethylthioand wherein at least one substituent is a halogen; R⁴ is a hydrogen orC₁-C₅ alkyl, each optionally independently substituted with one to threesubstituent groups, wherein each substituent group of R⁴ isindependently selected from halogen, hydroxy, oxo, cyano, amino, ortrifluoromethyl; R⁵ and R⁶ are each independently hydrogen, C₁-C₅ alkyl,or phenyl, or R⁵ and R⁶ together with the carbon atom they are commonlyattached to form a C₃-C₈ spiro cycloalkyl ring, each optionallyindependently substituted with one to three substituent groups, whereineach substituent group of R⁵ and R⁶ is independently selected fromhalogen, hydroxy, oxo, cyano, amino, or trifluoromethyl; and R⁷ is aheteroaryl group optionally independently substituted with one to threesubstituent groups, wherein each substituent group of R⁷ isindependently C₁-C₃ alkyl, C₂-C₅ alkenyl, C₂-C₅ alkynyl, heterocyclyl,aryl, heteroaryl, C₁-C₅ alkoxy, aminocarbonyl, C₁-C₃ alkylaminocarbonyl,C₁-C₃ dialkylaminocarbonyl, halogen, hydroxy, carboxy, cyano,trifluoromethyl, trifluoromethoxy, trifluoromethylthio, nitro, aminowherein the nitrogen atom is optionally independently mono- ordi-substituted by C₁-C₅ alkyl, or C₁-C₅ alkylthio wherein the sulfuratom is optionally oxidized to a sulfoxide or sulfone, wherein eachsubstituent group of R⁷ is optionally independently substituted with oneto three substituent groups selected from C₁-C₃ alkyl, C₁-C₃ alkoxy,aryl, acyl, acylamino, halogen, hydroxy, oxo, cyano, trifluoromethyl, oramino wherein the nitrogen atom is optionally independently mono- ordi-substituted by C₁-C₅ alkyl, or a tautomer, prodrug, solvate, or saltthereof.
 2. The compound of Formula (I) according to claim 1, wherein:R¹ is hydrogen; R² is a phenyl or naphthyl group, each optionallyindependently substituted with one to five substituent groups, whereineach substituent group of R² is independently C₁-C₃ alkyl, C₁-C₅ alkoxy,hydroxy, nitro, trifluoromethyl, trifluoromethoxy, halogen, cyano, C₁-C₅alkylthio, or amino wherein the nitrogen atom is optionallyindependently mono- or di-substituted by C₁-C₅ alkyl; R³ is C₁-C₅ alkylindependently substituted with two to five substituent groups, whereineach substituent group of R³ is C₃-C₈ cycloalkyl, halogen,trifluoromethyl, or trifluoromethoxy, and wherein at least twosubstituents are halogens; R⁴ is hydrogen; R⁵ and R⁶ are each hydrogenor C₁-C₅ alkyl; and R⁷ is an indolyl, azaindolyl, diazaindolyl,imidazolyl, dihydrobenzofuranyl, benzofuranyl, benzothienyl,benzimidazolyl, isoquinolinyl, quinolinyl, tetrahydroquinolinyl,tetrahydroquinoxalinyl, or pyridinyl group, each optionallyindependently substituted with one to three substituent groups, whereineach substituent group of R⁷ is independently C₁-C₃ alkyl, morpholinyl,piperdinyl, phenyl, pyridinyl, pyrimidinyl, C₁-C₃ alkoxy, aminocarbonyl,C₁-C₃ alkylaminocarbonyl, C₁-C₃ dialkylaminocarbonyl, fluoro, chloro,bromo, cyano, trifluoromethyl, or C₁-C₃ alkylthio wherein the sulfuratom is optionally oxidized to a sulfoxide or sulfone, wherein eachsubstituent group of R⁷ is optionally independently substituted with asubstituent group selected from methyl, methoxy, fluoro, chloro, bromo,oxo, or trifluoromethyl, or a tautomer, prodrug, solvate, or saltthereof.
 3. The compound of Formula (I) according to claim 1, wherein:R¹ is hydrogen; R² is a phenyl group, wherein each substituent group ofR² is independently C₁-C₅ alkyl, C₁-C₃ alkoxy, hydroxy, trifluoromethyl,trifluoromethoxy, halogen, cyano, C₁-C₃ alkylthio, or amino wherein thenitrogen atom is optionally independently mono- or di-substituted byC₁-C₃ alkyl; R³ is trifluoromethyl, pentafluoroethyl, —CH₂CF₃, or—CF₂CH₃; R⁴ is hydrogen; R⁵ and R⁶ are each hydrogen; and R⁷ is anindolyl, azaindolyl, tetrahydroquinolinyl, or tetrahydroquinoxalinylgroup, each optionally independently substituted with one to threesubstituent groups, wherein each substituent group of R⁷ isindependently C₁-C₃ alkyl, morpholinyl, piperdinyl, phenyl, pyridinyl,pyrimidinyl, C₁-C₃ alkoxy, fluoro, chloro, bromo, cyano,trifluoromethyl, or C₁-C₃ alkylthio wherein the sulfur atom isoptionally oxidized to a sulfoxide or sulfone, wherein each substituentgroup of R⁷ is optionally independently substituted with a substituentgroup selected from methyl, methoxy, fluoro, chloro, bromo, oxo, ortrifluoromethyl, or a tautomer, prodrug, solvate, or salt thereof.
 4. Acompound selected from:2,4,6-Trimethyl-N-[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;2,4,6-Trichloro-N-[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;2,4,6-Triisopropyl-N-[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;2-Amino-4,6-dichloro-N-[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;N-[2,2,2-Trifluoro-1-(1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;2,4,6-Trimethyl-N-[2,2,2-trifluoro-1-(7-methyl-1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;N-[1-(5-Cyano-1H-indol-3-ylmethyl)-2,2,2-trifluoroethyl]-2,4,6-trimethylbenzenesulfonamide;N-[1-(5-Bromo-1H-indol-3-ylmethyl)-2,2,2-trifluoroethyl]-2,4,6-trimethylbenzenesulfonamide;N-[1-(4-Bromo-1H-indol-3-ylmethyl)-2,2,2-trifluoroethyl]-2,4,6-trimethylbenzenesulfonamide;2,4,6-Trimethyl-N-[2,2,2-trifluoro-1-(1H-pyrrolo[3,2-b]pyridin-3-ylmethyl)ethyl]benzenesulfonamide;2,4,6-Trimethyl-N-[2,2,2-trifluoro-1-(4-methyl-1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;2,4,6-Trimethyl-N-[2,2,2-trifluoro-1-(6-methyl-1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;4-Bromo-2,6-dichloro-N-[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;2,4,6-Trimethyl-N-[2,2,2-trifluoro-1-(5-methyl-1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;2-Amino-4,6-dichloro-N-[2,2,2-trifluoro-1-(5-methyl-1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;Naphthalene-1-sulfonic acid[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]amide;Naphthalene-2-sulfonic acid[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]amide;5-Bromo-2-methoxy-N-[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;2-Methoxy-4-methyl-N-[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;2,4-Dichloro-6-methoxy-N-[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;2,4-Dichloro-6-hydroxy-N-[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;2-Amino-4,6-difluoro-N-[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;2-Amino-4,6-dimethyl-N-[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;2-Amino-4,6-dibromo-N-[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;2,4-Difluoro-6-hydroxy-N-[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;2-Hydroxy-4,6-dimethyl-N-[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;2,4-Dibromo-6-hydroxy-N-[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;2,4-Difluoro-6-methoxy-N-[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;2-Methoxy-4,6-dimethyl-N-[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;2,4-Dibromo-6-methoxy-N-[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;2-Amino-4,6-dichloro-N-[2,2,3,3,3-pentafluoro-1-(1H-indol-3-ylmethyl)propyl]benzenesulfonamide;2-Amino-4,6-difluoro-N-[2,2,3,3,3-pentafluoro-1-(1H-indol-3-ylmethyl)propyl]benzenesulfonamide;2-Amino-4,6-dimethyl-N-[2,2,3,3,3-pentafluoro-1-(1H-indol-3-ylmethyl)propyl]benzenesulfonamide;2-Amino-4,6-difluoro-N-[2,2,2-trifluoro-1-(5-methyl-1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;2-Amino-4,6-dimethyl-N-[2,2,2-trifluoro-1-(5-methyl-1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;2-Amino-4,6-dibromo-N-[2,2,2-trifluoro-1-(5-methyl-1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;2,4-Dichloro-6-hydroxy-N-[2,2,2-trifluoro-1-(5-methyl-1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;2-Amino-4,6-dichloro-N-[2,2,3,3,3-pentafluoro-1-(5-methyl-1H-indol-3-ylmethyl)propyl]benzenesulfonamide;2-Amino-4,6-dichloro-N-[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)-1-methylethyl]benzenesulfonamide;2-Amino-4,6-dichloro-N-[1-(2,3-dihydroindol-1-ylmethyl)-2,2,2-trifluoroethyl]benzenesulfonamide;2-Amino-4,6-dichloro-N-(2,2,2-trifluoro-1-indol-1-ylmethylethyl)benzenesulfonamide;2-Amino-4,6-dichloro-N-[1-(2,3-dihydrobenzofuran-7-ylmethyl)-2,2,2-trifluoroethyl]benzenesulfonamide;2-Amino-4,6-dichloro-N-[1-(3,4-dihydro-2H-quinolin-1-ylmethyl)-2,2,2-trifluoroethyl]-benzenesulfonamide;2-Amino-4,6-dichloro-N-[2,2-difluoro-1-(1H-indol-3-ylmethyl)propyl]benzenesulfonamide;2-Amino-4,6-dichloro-N-[3,3,3-trifluoro-1-(1H-indol-3-ylmethyl)propyl]benzenesulfonamide;and4-Amino-2,6-dichloro-N-[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]benzenesulfonamide,or a tautomer, prodrug, solvate, or salt thereof.
 5. A compound selectedfrom:2,4,6-Trimethyl-N-[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;2,4,6-Triisopropyl-N-[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;2-Amino-4,6-dichloro-N-[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;N-[2,2,2-Trifluoro-1-(1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;2,4,6-Trimethyl-N-[2,2,2-trifluoro-1-(7-methyl-1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;N-[1-(5-Cyano-1H-indol-3-ylmethyl)-2,2,2-trifluoroethyl]-2,4,6-trimethylbenzenesulfonamide;N-[1-(5-Bromo-1H-indol-3-ylmethyl)-2,2,2-trifluoroethyl]-2,4,6-trimethylbenzenesulfonamide;N-[1-(4-Bromo-1H-indol-3-ylmethyl)-2,2,2-trifluoroethyl]-2,4,6-trimethylbenzenesulfonamide;2,4,6-Trimethyl-N-[2,2,2-trifluoro-1-(1H-pyrrolo[3,2-b]pyridin-3-ylmethyl)ethyl]benzenesulfonamide;2,4,6-Trimethyl-N-[2,2,2-trifluoro-1-(4-methyl-1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;2,4,6-Trimethyl-N-[2,2,2-trifluoro-1-(6-methyl-1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;4-Bromo-2,6-dichloro-N-[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;2,4,6-Trimethyl-N-[2,2,2-trifluoro-1-(5-methyl-1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;2-Amino-4,6-dichloro-N-[2,2,2-trifluoro-1-(5-methyl-1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;Naphthalene-1-sulfonic acid[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]amide;Naphthalene-2-sulfonic acid[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]amide;5-Bromo-2-methoxy-N-[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;2-Methoxy-4-methyl-N-[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;2,4-Dichloro-6-methoxy-N-[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;and2,4-Dichloro-6-hydroxy-N-[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]benzenesulfonamide,or a tautomer, prodrug, solvate, or salt thereof.
 6. A compound selectedfrom:2,4,6-Trimethyl-N-[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;2,4,6-Triisopropyl-N-[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;2-Amino-4,6-dichloro-N-[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;2,4,6-Trimethyl-N-[2,2,2-trifluoro-1-(7-methyl-1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;N-[1-(5-Cyano-1H-indol-3-ylmethyl)-2,2,2-trifluoroethyl]-2,4,6-trimethylbenzenesulfonamide;N-[1-(5-Bromo-1H-indol-3-ylmethyl)-2,2,2-trifluoroethyl]-2,4,6-trimethylbenzenesulfonamide;N-[1-(4-Bromo-1H-indol-3-ylmethyl)-2,2,2-trifluoroethyl]-2,4,6-trimethylbenzenesulfonamide;2,4,6-Trimethyl-N-[2,2,2-trifluoro-1-(1H-pyrrolo[3,2-b]pyridin-3-ylmethyl)ethyl]benzenesulfonamide;2,4,6-Trimethyl-N-[2,2,2-trifluoro-1-(4-methyl-1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;2,4,6-Trimethyl-N-[2,2,2-trifluoro-1-(6-methyl-1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;4-Bromo-2,6-dichloro-N-[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;2,4,6-Trimethyl-N-[2,2,2-trifluoro-1-(5-methyl-1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;2-Amino-4,6-dichloro-N-[2,2,2-trifluoro-1-(5-methyl-1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;Naphthalene-1-sulfonic acid[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]amide;Naphthalene-2-sulfonic acid[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]amide;2-Methoxy-4-methyl-N-[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;2,4-Dichloro-6-methoxy-N-[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;and2,4-Dichloro-6-hydroxy-N-[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]benzenesulfonamide,or a tautomer, prodrug, solvate, or salt thereof.
 7. A compound selectedfrom:2,4,6-Trimethyl-N-[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;2,4,6-Triisopropyl-N-[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;2-Amino-4,6-dichloro-N-[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;2,4,6-Trimethyl-N-[2,2,2-trifluoro-1-(7-methyl-1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;N-[1-(5-Bromo-1H-indol-3-ylmethyl)-2,2,2-trifluoroethyl]-2,4,6-trimethylbenzenesulfonamide;N-[1-(4-Bromo-1H-indol-3-ylmethyl)-2,2,2-trifluoroethyl]-2,4,6-trimethylbenzenesulfonamide;2,4,6-Trimethyl-N-[2,2,2-trifluoro-1-(4-methyl-1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;2,4,6-Trimethyl-N-[2,2,2-trifluoro-1-(6-methyl-1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;4-Bromo-2,6-dichloro-N-[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;2,4,6-Trimethyl-N-[2,2,2-trifluoro-1-(5-methyl-1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;2-Amino-4,6-dichloro-N-[2,2,2-trifluoro-1-(5-methyl-1H-indol-3-ylmethyl)ethyl]benzenesulfonamide;and2,4-Dichloro-6-methoxy-N-[2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethyl]benzenesulfonamide,or a tautomer, prodrug, solvate, or salt thereof.
 8. A pharmaceuticalcomposition comprising an effective amount of a compound according toone of claims 1 to 7, or a tautomer, prodrug, solvate, or salt thereof,and a pharmaceutically acceptable excipient or carrier.
 9. A method ofmodulating the glucocorticoid receptor function in a patient, the methodcomprising administering to the patient an effective amount of apharmaceutically acceptable compound according to one of claims 1 to 7,or a tautomer, prodrug, solvate, or salt thereof.
 10. A method oftreating a disease-state or condition mediated by the glucocorticoidreceptor function in a patient in need of such treatment, the methodcomprising administering to the patient an effective amount of apharmaceutically acceptable compound according to one of claims 1 to 7,or a tautomer, prodrug, solvate, or salt thereof.
 11. A method oftreating a disease-state or condition selected from: type II diabetes,obesity, cardiovascular diseases, hypertension, arteriosclerosis,neurological diseases, adrenal and pituitary tumors, and glaucoma, in apatient in need of such treatment, the method comprising administeringto the patient an effective amount of a pharmaceutically acceptablecompound according to one of claims 1 to 7, or a tautomer, prodrug,solvate, or salt thereof.
 12. A method of treating a diseasecharacterized by inflammatory, allergic, or proliferative processes, ina patient in need of such treatment, the method comprising administeringto the patient an effective amount of a pharmaceutically acceptablecompound according to one of claims 1 to 7, or a tautomer, prodrug,solvate, or salt thereof.
 13. The method according to claim 12, whereinthe disease is selected from: (i) lung diseases; (ii) rheumaticdiseases/autoimmune diseases/joint diseases; (iii) allergic diseases;(iv) vasculitis diseases; (v) dermatological diseases; (vi) renaldiseases; (vii) hepatic diseases; (viii) gastrointestinal diseases; (ix)proctological diseases; (x) eye diseases; (xi) diseases of the ear,nose, and throat (ENT) area; (xii) neurological diseases; (xiii) blooddiseases; (xiv) tumor diseases; (xv) endocrine diseases; (xvi) organ andtissue transplantations and graft-versus-host diseases; (xvii) severestates of shock; (xviii) substitution therapy; and (xix) pain ofinflammatory genesis.
 14. The method according to claim 12, wherein thedisease is selected from: type I diabetes, osteoarthritis,Guillain-Barre syndrome, restenosis following percutaneous transluminalcoronary angioplasty, Alzheimer disease, acute and chronic pain,atherosclerosis, reperfusion injury, bone resorption diseases,congestive heart failure, myocardial infarction, thermal injury,multiple organ injury secondary to trauma, acute purulent meningitis,necrotizing enterocolitis, and syndromes associated with hemodialysis,leukopheresis, and granulocyte transfusion.
 15. A method of treating adisease-state or condition mediated by the glucocorticoid receptorfunction in a patient in need of such treatment, the method comprisingsequentially or simultaneously administering to the patient: (a) aneffective amount of a pharmaceutically acceptable compound according toone of claims 1 to 7 or a tautomer, prodrug, solvate, or salt thereof,and (b) a pharmaceutically acceptable glucocorticoid.
 16. A kit for thein vitro diagnostic determination of the glucocorticoid receptorfunction in a sample, comprising: (a) a diagnostically effective amountof a compound according to claim 1 or a tautomer, prodrug, solvate, orsalt thereof, and (b) instructions for use of the diagnostic kit.
 17. Amethod of making a compound of Formula (I)

where R¹ is H and R², R³, R⁴, R⁵, R⁶, and R⁷ are as defined in claim 1,the method comprising reacting an aziridine compound of Formula (II)with an organometallic reagent R⁷-M of Formula (III) where M is Na, Li,or MgX and X is Cl, Br, or I, in a suitable solvent to form the compoundof Formula (I)


18. A method of making a compound of Formula (I)

where R¹, R⁴, R⁵, and R⁶ are each H, and R², R³, and R⁷ are as definedin claim 1, the method comprising: (a) reacting an epoxide of Formula(IV) with sodium azide in a suitable solvent such as ethanol-water inthe presence ammonium chloride to provide an azide of Formula (V)

(b) reducing the azide of Formula (V) with hydrogen in the presence of asuitable catalyst such as palladium on carbon in a suitable solvent suchas methanol to form an amino alcohol of Formula (VI)

(c) reacting the amino alcohol of Formula (VI) with a sulfonyl chlorideof Formula (VII) in a suitable solvent such as tetrahydrofuran in thepresence of a base such as sodium hydride or in dichloromethane in thepresence of pyridine followed by a suitable base such as aqueouspotassium hydroxide to form an aziridine of Formula (VIII)

(d) reacting the aziridine of Formula (VIII) with an organometallicreagent R⁷-M of Formula (III) where M is Na, Li, or MgX and X is Cl, Br,or I, in a suitable solvent such as ether, tetrahydrofuran, or DMF toform the compound of Formula (I)


19. A method of making a compound of Formula (I)

where R¹, R⁴, R⁵, and R⁶ are each H, and R², R³, and R⁷ are as definedin claim 1, the method comprising: (a′) reacting a sulfonamide when R²is an ortho- or para-substituted nitrophenyl with a thiol such asthiophenol in the presence of a base such as potassium carbonate in DMFor, when R² is a 2,4,6-trimethyl-substituted phenyl, with magnesiummetal in a suitable solvent such as methanol under sonication to form anamine of Formula (IX)

(b′) reacting the aminoethyl compound of Formula (IX) with a sulfonylhalide of Formula (VII) in the presence of a suitable base to form thecompound of Formula (I)


20. A method of making a compound of Formula (I)

where R¹, R², R³, R⁴, R⁵, R⁶, and R⁷ are as defined in claim 1, themethod comprising: (a) reacting a bromoketone of Formula (X) withhydroxylamine hydrochloride in chloroform-water or ethanol-water to forman oxime of Formula (XI)

(b) reacting the oxime of Formula (XI) with an indole or azaindole(where R⁷ is indole) of Formula (XII) in the presence of a suitable basein a suitable solvent such as dichloromethane or tert-butyl methyl etherto form the intermediate of Formula (XIII)

(c) reducing the oxime of Formula (XIII) with a suitable reducing agentsuch a lithium aluminum hydride in a suitable solvent such as ether orTHF to form a compound of Formula (XIV)

(d) reacting the intermediate of Formula (XIV) with a sulfonyl halide ofFormula (VII) in the presence of a suitable base to form the compound ofFormula (I)